Clinical trial NCT04269889
Conditions: Anemia, Diamond-Blackfan
Keywords: Chelation, Ribosomopathy Erythroid Aplasia Iron Homeostasis Hemoglobin Synthesis Heme Synthesis
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2020-12-01; Completion date: 2024-02-16
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Diamond-Blackfan anemia (DBA) is treated with steroids. But some people cannot take steroids, or steroids don t work. Other patients must get blood transfusions regularly which are time consuming and can have significant side effects. The drug eltrombopag can increase red blood cells. Researchers want to see if it can help people with DBA and, if so, for how long.

Objective:

To study the safety and efficacy of eltrombopag in people with DBA who have not responded to steroids or could not take them.

Eligibility:

People ages 2 and older with DBA who did not respond to steroids or could not take them, or their disease has returned despite taking them

Design:

Participants will be screened with:

Medical and medicine history

Physical exam

MRI: Participants will lie in a machine that takes pictures of the liver.

Blood and urine tests

Bone marrow biopsy: A thin needle will remove a marrow sample from the participant's hip bone.

Electrocardiogram

Participants will take eltrombopag pills once daily for 24 weeks. They will have blood taken every 2 weeks.

Participants will have visits 6 months. At 6 months, they will repeat all the screening tests and also have:

Quality-of-life questionnaire

Neurodevelopmental test (for participants younger than 18 years)

If participants blood cell counts improve, they may keep taking eltrombopag for up to 3 more years. If so, they will have blood taken every 4 weeks. They will visit NIH every 6 months and repeat the above tests.

Participants will be monitored for up to 3 years after they stop taking eltrombopag. They will visit NIH 6 months after treatment ends. If participants blood counts go down after treatment ends, they may restart the drug....

Detailed description:
Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure (BMF) syndrome characterized by selective erythroid defects typically presenting within the first year of life as a normochromic, macrocytic anemia with reticulocytopenia. More than half of all DBA cases are associated with either inherited or spontaneous mutations in ribosomal proteins, making DBA a prototypic ribosomopathy. Furthermore, although the primary presentation is isolated anemia, as life expectancy has improved, progressive defects in other lineages have now been identified, consistent with a long-term stem cell defect. Current standard of care for DBA is the use of systemic corticosteroids, the mechanism of which is unclear, although only half show an initial response. Even when a response to steroids is observed, long-term steroid therapy carries significant morbidity, especially in children or in combination with transfusion-associated iron overload, and thus most cannot tolerate high-dose steroids long-term. Responses are rare with second-line immunomodulatory agents. Yet other than allogeneic hematopoietic stem cell transplantation in those patients with healthy matched donors, there are no alternative therapies.

In one model for DBA pathogenesis, the defects lead to an overabundance of the iron-carrying moiety heme in primitive erythroid cells, unbound by protein. Free heme is toxic to cells, likely exacerbated over time by iron overload due to transfusions. Ongoing work with eltrombopag (EPAG) has shown that it is capable of acting as a potent iron chelator, including intracellular iron, with evidence that this effect of EPAG can reverse the impact of excess heme and elevated reactive oxygen species. Furthermore, in a recent trial of EPAG for moderate aplastic anemia or hypoproliferative unilineage cytopenias, we identified a robust response to EPAG in the one DBA patient enrolled in this clinical trial. This response has been durable over more than three years since study entry, but requires continuous EPAG to maintain transfusion independence. From these data, we hypothesize that EPAG may be able to improve production of red blood cells in DBA patients via chelation of iron and subsequent reduction in heme synthesis, resulting in decreased toxicity to bone marrow stem cells and developing erythroid cells.

We will conduct a single-arm, pilot trial in patients with steroid-refractory or steroid-intolerant DBA, treating with a fixed dose of EPAG for 6 months to assess safety and efficacy at improving hematological manifestations of DBA. Responders at 6 months will be able to continue EPAG on the extension part of this protocol for an additional 3 years. We will examine the hematologic, molecular, cytogenetic and clonal responses to EPAG in responders and non-responders alike. Translational studies will examine the mechanism of activity of EPAG in DBA through its effects on iron metabolism, erythroid differentiation, apoptosis, global transcriptome and TPO signaling pathways in patient's hematopoietic stem and progenitor cells (HSPCs).

Arms: arm 1: Participants with Refractory Diamond-Blackfan Anemia will be administered Eltrombopag. Participants 12 years of age an above will receive the adult dose of 150 mg by mouth daily. Participants between ages of 6 and 11 years old will start at 75 mg by mouth daily, and children 2 and 5 years of age will start at 2.5 mg/kg, not to exceed 75 mg by mouth daily.

To adjust for the higher expected exposure in participants of East Asian and South East Asian ancestry, the starting dose for East Asian and South East Asian participants 12 years of age and above will be 75 mg by mouth once daily. For East Asian and South East Asian participants between 6 and 11 years of age, the starting dose will be 37.5 mg once daily by mouth, and for children between 2 and 5, the starting dose will be 1.25 mg/kg by mouth.
Interventions: intervention 1: Eltrombopag
Intervention descriptions: intervention 1: Eltrombopag will be administered to participants 12 years of age an above will receive the adult dose of 150 mg by mouth daily. Participants between ages of 6 and 11 years old will start at 75 mg by mouth daily, and children 2 and 5 years of age will start at 2.5 mg/kg, not to exceed 75 mg by mouth daily.

To adjust for the higher expected exposure in participants of East Asian and South East Asian ancestry, the starting dose for East Asian and South East Asian participants 12 years of age and above will be 75 mg by mouth once daily. For East Asian and South East Asian participants between 6 and 11 years of age, the starting dose will be 37.5 mg once daily by mouth, and for children between 2 and 5, the starting dose will be 1.25 mg/kg by mouth.

Protocol documents:
Prot_SAP_001.pdf: 
 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
 
Treatment of refractory Diamond-Blackfan anemia with eltrombopag 
NCT number: 
 
NCT04269889 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
June 7, 2023 
 


Page 1 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
CLINICAL RESEARCH PROJECT
Protocol # 
20-H-0021
IND #
104877
IND Sponsor: NHLBI OCD
Date:
June 7, 2023
Title:
Treatment of refractory Diamond-Blackfan anemia with eltrombopag
Short Title:
Eltrombopag for Diamond-Blackfan anemia
Other 
Identifying 
Words:
Diamond-Blackfan 
anemia, 
erythroid 
aplasia, 
iron 
homeostasis, 
chelation, 
ribosomopathy, heme synthesis, hemoglobin synthesis, hematopoiesis, CD34, 
pancytopenia, anemia, thrombocytopenia, inherited bone marrow failure, Promacta 
(eltrombopag)
Principal Investigator:
David J Young, M.D., Ph. D., TSCBB, NHLBI (E)
301-827-7823
Bldg. 10, CRC 5-3150
Medically Advisory and Accountable Investigator:
Cynthia E. Dunbar, M.D., Chief, TSCBB, NHLBI (E)
301-496-5093
Bldg. 10, CRC 5-3332
Subjects in study:
Number
Gender
Age range
25 eligible subjects 
(Accrual Ceiling 30)
M/F
2 and older
Multicenter trial:
No
Ionizing Radiation:
No (Medically indicated only)
Off-Site Project:
No
DSMB Involvement:
Yes
Tech Transfer:
Yes (Novartis, CRADA)
IND:
Yes 


Page 2 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
Synopsis
Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure (BMF) syndrome 
characterized by selective erythroid defects typically presenting within the first year of life as a 
normochromic, macrocytic anemia with reticulocytopenia. More than half of all DBA cases are 
associated with either inherited or spontaneous mutations in ribosomal proteins, making DBA a 
prototypic “ribosomopathy”. Furthermore, although the primary presentation is isolated anemia, 
as life expectancy has improved, progressive defects in other lineages have now been identified, 
consistent with a long-term stem cell defect. Current standard of care for DBA is the use of systemic 
corticosteroids, the mechanism of which is unclear, although only half show an initial response. 
Even when a response to steroids is observed, long-term steroid therapy carries significant 
morbidity, especially in children or in combination with transfusion-associated iron overload, and 
thus most cannot tolerate high-dose steroids long-term. Responses are rare with second-line 
immunomodulatory agents. Yet other than allogeneic hematopoietic stem cell transplantation in 
those patients with healthy matched donors, there are no alternative therapies.
In one model for DBA pathogenesis, the defects lead to an overabundance of the iron-carrying 
moiety heme in primitive erythroid cells, unbound by protein. Free heme is toxic to cells, likely 
exacerbated over time by iron overload due to transfusions. Ongoing work with eltrombopag 
(EPAG) has shown that it is capable of acting as a potent iron chelator, including intracellular iron, 
with evidence that this effect of EPAG can reverse the impact of excess heme and elevated reactive 
oxygen species. Furthermore, in a recent trial of EPAG for moderate aplastic anemia or 
hypoproliferative unilineage cytopenias, we identified a robust response to EPAG in the one DBA 
patient enrolled in this clinical trial. This response has been durable over more than three years 
since study entry but requires continuous EPAG to maintain transfusion independence. From 
these data, we hypothesize that EPAG may be able to improve production of red blood cells in DBA 
patients via chelation of iron and subsequent reduction in heme synthesis, resulting in decreased 
toxicity to bone marrow stem cells and developing erythroid cells.
We will conduct a single-arm, pilot trial in patients with steroid-refractory or steroid-intolerant 
DBA, treating with a fixed dose of EPAG for 6 months to assess safety and efficacy at improving 
hematological manifestations of DBA. Responders at 6 months will be able to continue EPAG on 
the extension part of this protocol for an additional 3 years. We will examine the hematologic, 
molecular, cytogenetic and clonal responses to EPAG in responders and non-responders alike. 
Translational studies will examine the mechanism of activity of EPAG in DBA through its effects 
on iron metabolism, erythroid differentiation, apoptosis, global transcriptome and TPO signaling 
pathways in patient’s hematopoietic stem and progenitor cells (HSPCs).


Page 3 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
Table of Contents
Statement of Compliance ..............................................................................................................................................5
1.
Objectives .................................................................................................................................................................6
2.
Background and Scientific Justification .........................................................................................................6
2.1.
Pathophysiology of Diamond-Blackfan Anemia...................................................................................................6
2.2.
Clinical Features and Current Treatment Options..............................................................................................8
2.3.
Thrombopoietin and Hematopoiesis......................................................................................................................11
2.4.
Eltrombopag......................................................................................................................................................................12
2.5.
Scientific and clinical justification of the protocol............................................................................................20
3.
Study Design..........................................................................................................................................................22
4.
Eligibility Assessment........................................................................................................................................23
4.1.
Inclusion criteria.............................................................................................................................................................23
4.2.
Exclusion criteria ............................................................................................................................................................23
5.
Treatment Plan ....................................................................................................................................................27
5.1.
Administration of study drug (eltrombopag).....................................................................................................27
5.2.
Dose adjustments of eltrombopag...........................................................................................................................28
5.3.
Taper of eltrombopag in the extension protocol...............................................................................................28
5.4.
Dose delays, modifications or discontinuation for non-hematologic side effects ..............................29
5.5.
Dose delays, modifications or discontinuation for hematologic side effects........................................30
5.6.
Extended access to study drug..................................................................................................................................30
5.7.
Permitted supportive care..........................................................................................................................................30
5.8.
Non-permitted medications.......................................................................................................................................30
5.9.
Concurrent medications...............................................................................................................................................31
5.10.
Instructions to patients................................................................................................................................................32
5.11.
Health Related Quality of Life (HRQL) Questionnaires ..................................................................................32
6.
Clinical Evaluations.............................................................................................................................................32
6.1.
Pre-study evaluation .....................................................................................................................................................33
6.2.
Baseline labs......................................................................................................................................................................34
6.3.
On-Study evaluations (through 6 months ± 10 days).....................................................................................35
6.4.
Landmark 3-month and 6-month evaluations...................................................................................................35
6.5.
Long term follow-up for responding patients enrolled in extended access phase.............................36
6.6.
Off study assessment.....................................................................................................................................................38
6.7.
MRI Imaging to Assess Iron Loading......................................................................................................................39
6.8.
Genetic analysis ...............................................................................................................................................................40


Page 4 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
7.
Laboratory Research Studies ..........................................................................................................................41
8.
Biostatistical Considerations...........................................................................................................................43
8.1.
Objectives...........................................................................................................................................................................43
8.2.
Endpoints ...........................................................................................................................................................................43
8.3.
Sample size ........................................................................................................................................................................45
8.4.
Statistical methods.........................................................................................................................................................45
8.5.
Stopping rules...................................................................................................................................................................46
8.6.
Off study criteria..............................................................................................................................................................47
9.
Data and Safety Monitoring..............................................................................................................................49
9.1.
Safety Monitoring............................................................................................................................................................49
9.2.
Event Characterization and Reporting ..................................................................................................................50
9.3.
Reporting Serious Adverse Events to Novartis..................................................................................................55
9.4.
Reporting of pregnancy................................................................................................................................................56
9.5.
Data management...........................................................................................................................................................56
9.6.
Future use of biospecimens........................................................................................................................................59
10.
Human Subject Protection...........................................................................................................................59
10.1.
Rationale for subject selection..................................................................................................................................59
10.2.
Participation of Pediatric patients...........................................................................................................................64
10.3.
Risks and Discomforts ..................................................................................................................................................64
10.4.
Risks in Relation to Benefit.........................................................................................................................................77
10.5.
Informed Consent Processes and Procedures....................................................................................................78
10.6.
Conflict of Interest..........................................................................................................................................................81
10.7.
Collaborative Agreements...........................................................................................................................................81
11.
Pharmaceuticals..............................................................................................................................................82
11.1.
Eltrombopag (Promacta®).........................................................................................................................................82
12.
References.........................................................................................................................................................85
13.
Appendices........................................................................................................................................................92
APPENDIX A: Schedule of Activities .......................................................................................................................................92
APPENDIX B: Collection of samples for PK Assessments..............................................................................................97


Page 5 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
Statement of Compliance
This trial will be carried out in accordance with International Conference on Harmonization 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 forms, 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 
amendment 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.


Page 6 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
1. Objectives
The primary objective is to evaluate safety and efficacy of eltrombopag in subjects with Diamond-
Blackfan anemia.
The secondary objectives include assessments of the impact of eltrombopag upon rates of relapse 
and survival, clonal evolution, toxicities of extended therapy, the impact of treatment upon health-
related quality of life and neurodevelopment in pediatric patients, and the impact of eltrombopag 
upon stem cell and erythroid cell dynamics and niche interactions including iron homeostasis.
2. Background and Scientific Justification
2.1.
Pathophysiology of Diamond-Blackfan Anemia
Diamond-Blackfan anemia (DBA) is a rare, autosomal dominant (rarely X-linked) inherited bone 
marrow failure syndrome (BMFS) characterized by selective erythroid defects presenting early in 
life, usually in the perinatal period or first year of life. Mutations in numerous genes can be linked 
to the pathophysiology of DBA in more than 60% of cases. Among the genes identified are GATA1 
and FLVCR1; however, in over three-quarters of cases with an identified mutation, the disease has 
been conclusively linked to inherited or spontaneous mutations in 19 of the 79 genes coding 
ribosomal proteins (RP) (1-3). The most common of these, encompassing approximately half of all 
identified cases, are RPS19 (25%), RPL5 (7%), RPS26 (6.6%), and RPL11 (5%) (4). Further 
emphasizing the role of ribosomal biogenesis in DBA, the RPS26 chaperone protein, TSR2 has also 
been linked to cases of DBA. DBA is often referred to as a prototypic “ribosomopathy”, because of 
its intimate link to ribosomal biogenesis. That the disease arises from a general loss-of-function 
disruption of ribosomes is suggested by the fact that RP mutations are rarely duplicated in non-
related cases. Indeed, over 80% of DBA cases present with a novel RP mutation. Although 15-20% 
of cases are familial with high penetrance in the most commonly affected genes, the majority of 
cases are sporadic heterozygous germline mutations.
As noted above, most cases of DBA, especially those linked to RP, are dominantly-inherited. More 
specifically, mutation of a single allelic copy is sufficient to produce disease, a condition referred 
to as haploinsufficiency. Homozygous inactivation of an RP gene would be expected to be 
embryonically lethal. Instead, the biosynthesis of ribosomes requires such precise balancing of the 
different components that loss of a single copy of even one gene, at least the 19 genes thus far 
implicated in DBA, is sufficient to cause disease (3). However, the exact mechanism by which 
disruption of the stoichiometry of ribosome biogenesis specifically leads to failure of erythroid 
maturation has remained unclear until recently.
In an emerging model for DBA, it is hypothesized that the imbalance in ribosomal subunits impacts 
the kinetics of the synthesis of the globin chain of hemoglobin in red blood cells. Under normal 


Page 7 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
steady-state conditions, the synthesis of the protein components of hemoglobin are exquisitely 
matched to that of the iron-carrying heme moiety (5). However, the ribosomal defect in the 
primitive erythroid cells of DBA patients leads to an asynchrony between globin chain and heme 
biosynthesis (6). An excess of free heme thus develops in these primitive cells, which in turn leads 
to an accumulation of protein-free iron. The consequence of these imbalances is the production of 
reactive oxygen species within the sensitive developing erythrocyte, leading to a loss of the 
erythroid lineage and the clinical presentation of pure red cell aplasia. In addition, a major 
component of DBA therapy is chronic transfusions (see §2.2), which in time cause whole-body iron 
loading, and likely exacerbate the iron-mediated oxidative stress in developing erythroid cells, in 
addition to the other clinical consequences of iron overloading, as discussed below.
Although it is only within the erythrocytes that the subtle imbalance in ribosomal biology leads 
directly to such a profoundly toxic metabolic disruption, it is unlikely that the ribosomal effects of 
DBA-associated mutations are restricted to the erythroid lineages of the bone marrow. Likely 
similar but more subtle disruptions in protein synthesis in other lineages, especially at critical 
points in embryogenesis and early development, lead to some of the phenotypic changes and 
dysmorphisms seen in some subtypes of DBA. Furthermore, although the primary presentation is 
isolated anemia, as improved supportive care has increased the life expectancy of DBA patients, 
progressive defects in other lineages have now been identified, consistent with a long-term stem 
cell defect (7). Several mechanisms are likely involved. This may partially be a consequence of the 
cumulative effects of disordered protein synthesis slowly disrupting other pathways, but with less 
toxic impact than excess erythroid heme. Additionally, there is growing evidence that the effects 
of heme accumulation and iron toxicity are not confined intracellularly. Erythrocytes cells develop 
in erythroblastic islands (EI), aggregates of developing erythroid progenitors surrounding a 
central macrophage. Within the context of close cellular contact, the oxidative stresses can spread 
from the affected progenitor, first poisoning adjacent progenitors, the associated macrophage, and 
eventually other primitive cells within the greater hematopoietic niche.
The role of heme biosynthesis and oxidative stress has been further supported by work on non-
ribosomal DBA. Feline leukemia virus subgroup C receptor-related protein 1 (FLVCR1), is a 
transport protein that facilitates the export of free cytoplasmic heme. Its mutation has been linked 
to a non-canonical form of DBA (8). In Flvcr1 mutated mice, free heme cannot be efficiently cleared 
from the cells during hemoglobin synthesis, leading to an accumulation reminiscent of the RP-
mutated forms of DBA, with similar downstream consequences (9, 10). Furthermore, work with 
both FLVCR1 and GATA1 have demonstrated a feedback loop between the two proteins, with the 
assistance of various chaperones that further regulate heme synthesis, heme efflux, and globin 
translation further underscoring the importance of balancing the components of hemoglobin and 
providing a model by which ribosome biology, cell signaling, and metabolism intersect to produce 
disease (11, 12).


Page 8 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
2.2.
Clinical Features and Current Treatment Options
Typically, DBA presents as an isolated, macrocytic anemia of early childhood. As it is a BMFS, this 
anemia is accompanied by a lack of marrow precursors and reticulocytes, circulating immature 
erythrocytes. In the overwhelming majority of patients (>90%), the hematopoietic defects are 
noted within the first year of life. Indeed, in rare, severe cases, DBA can present as fatal anemia in 
the neonatal period following early stressors such as the physiologic nadir, or even as hydrops 
fetalis. These features make up the diagnostic tetrad that defines DBA:
1. Presentation within the first year of life;
2. Macrocytic anemia without other significant cytopenias;
3. Reticulocytopenia; and
4. A paucity of bone marrow erythroid precursors, but with otherwise preserved marrow 
architecture.
In some cases, onset of signs and symptoms before the first year of life may only be recognized in 
retrospect in later childhood during disease progression, as the erythroid derangements may be 
subtle and asymptomatic. In other cases, the hematologic features may be part of a larger spectrum 
of findings that include congenital malformations, sometimes despite mild or even absent anemia. 
The diagnosis of DBA requires exclusion of other disorders such as transient erythroblastopenia 
of childhood (typically normocytic, and affecting older toddlers), dyskeratosis congenita and other 
telomeropathies, Fanconi anemia, Schwachman-Bodian-Diamond syndrome, infections, toxic 
exposures, and nutritional defects. Diagnosis may be aided by family history or positive genetic 
testing of known DBA-associated genes. However, as noted above, less than half of cases are 
inherited, a causative mutation will not be identified in approximately one-third of cases, and even 
when found, as many as four-fifths of all mutations will be unique to that family, complicating 
definitive identification. For this reason, DBA is a clinical diagnosis, supported by 
hematopathologic investigations.
In addition to the hematologic changes, DBA is often associated with congenital abnormalities. 
Whereas RPS19 patients do not demonstrate consistent patterns of developmental defects (13), 
considerably higher rates of physical malformations are identified in patients with RPL5 (83%) 
and RPL11 (73%) mutations, with RPL5 tending towards more severe phenotypes (14). These 
include a five- to six-fold higher rate of cardiac malformations (ranging from septal defects to 
tetralogy of Fallot). RPL11 and RPL5 mutations are strongly associated with hand defects (often 
thumb) and craniofacial abnormalities (especially cleft lift and palate), respectively, with similar 
albeit weaker associations of each mutation for the opposite spectrum of abnormalities (14, 15). 
Although approximately one-half of RPS19 patients will have an identifiable congenital 
abnormality, there is no specific genotype-phenotype correlation, they are often milder, and 


Page 9 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
usually occur in isolation, whereas RPL5 and RPL11 patients frequently present with multiple 
abnormalities.
Although DBA presents early in life, it is a lifetime condition. This is, of course, due in part to the 
chronicity of the anemia and the developmental defects. However, as supportive care and 
treatments have improved life expectancy, it has become apparent that DBA is associated with 
other complications that tend to present later in life. With time, additional, progressive cytopenias 
may develop (7). The most frequent of these is thrombocytopenia; however, neutropenia has been 
reported, with some patients progressing to aplastic anemia. Additionally, DBA patients are at 
increased risk for developing myelodysplastic syndrome (MDS) at a rate over 300-fold higher than 
expected and acute myeloid leukemia (AML) at an almost 30-fold higher rate than expected, with 
diagnoses occurring as early as the first or second decades of life for what is typically considered 
an adult cancer (16, 17). Indeed, when considering hematopoietic stem cell transplant (HSCT) as 
definitive therapy (see below), all related donors need to be tested for DBA, even if clinical signs 
and symptoms are absent, as donation from an affected patient carries the risk of engraftment 
failure, primary graft failure even beyond the peri-transplant period, or subsequent evolution to 
MDS and/or AML.
DBA is a cancer-predisposition beyond hematologic malignancies. Patients are at risk for 
carcinomas and sarcomas, including, but not limited to, gastric and colon cancer, lymphoma, 
osteogenic sarcoma, and breast cancer (16-18). Yet, similar to other BMFS, oncologic treatments 
are often complicated by prolonged cytopenias and other chemotherapeutic toxicities. Cancer 
surveillance and optimal treatment modifications for these patients remains uncertain.
Effective treatment of DBA is currently limited to three options:
1. Corticosteroid therapy
2. Chronic transfusions
3. Hematopoietic stem cell transplant (HSCT)
The current standard of care for DBA is systemic corticosteroids. Ideally steroid initiation is 
delayed until after the end of the first year of life, to avoid developmental effects, especially in a 
population already at risk for altered growth and development. Initial response to steroid therapy 
is often within weeks of starting therapy, and is observed in 75-80% of patients (18, 19); however, 
primary refractory disease is seen in approximately one-fifth of patients. Even in responders, 
relapse or discontinuation of therapy due to side effects is common, and durable, steroid-
independent remission is rare. In long-term longitudinal studies of the Diamond-Blackfan Anemia 
Registry (DBAR), 40% of patients remain steroid-dependent, and 40% are transitioned to chronic 
transfusion therapy for either steroid intolerance or relapsed/refractory disease. Only one-fifth of 
patients maintain remission without steroids or HSCT (18). Long-term steroid therapy carries 


Page 10 of 97
P#: 20-H-0021
PI: David J. Young, M.D., Ph.D.
Date: 06/07/2023
significant side-effects and risks including growth retardation, metabolic syndrome with 
hyperglycemia and diabetes, osteopenia complicated by pathologic fractures and avascular 
necrosis, hypertension, and cataracts.
Chronic transfusion therapy is frequently initiated for DBA due to intolerance of the long-term 
consequences of steroids. Although the infectious risk of a chronic transfusion regimen has been 
significantly minimized in recent decades, such treatments remain burdensome due to their 
frequency, the risk of alloimmunization (which can complicate subsequent HSCT), and iron 
loading. It is this iron loading, progressing to clinically significant iron overload (secondary 
hemochromatosis), that carries some of the greatest long-term risk for DBA patients, especially 
non-transplant morbidity and mortality.
Secondary hemochromatosis is a systemic complication encountered in many diseases treated via 
chronic transfusions including sickle cell anemia, thalassemia, and Fanconi anemia. Under normal 
homeostatic conditions, iron is very efficiently recycled through macrophages within the 
reticuloendothelial system, and as a result, the overall nutritional iron requirements in a healthy, 
non-bleeding adult are relatively small (approximately 1 mg daily). Even in the developing child, 
the nutritional requirements are easily met. However, a single unit of packed erythrocytes can 
contain 200-250 mg of iron, roughly equivalent to 6-8 months-worth of iron intake. Although acute 
transfusions are typically undertaken in the setting of blood loss, offsetting this iron infusion, in 
chronic transfusion, the additive consequence of these transfusions is systemic iron loading. 
Significant iron loading and subsequent tissue deposition can be seen after just 10 transfusions, 
and overload (15 mg iron per gram of liver, dry weight) is seen after 20 transfusions, a threshold 
typically met within the first year of starting transfusions. In the overloaded state, iron is 
depositing in various tissues. The most concerning organs are the liver and the heart, where 
dysfunction of either can be life-threatening beginning at tissue iron levels seen by the end of that 
first year; however, endocrine dysfunction can be significant, especially in the thyroid and 
pancreas.
Biopsy has historically been used to measure the liver iron concentration (LIC), and as such has 
served as a measure of total body iron concentration. It is generally considered the “gold standard” 
for assessing iron load and is more accurate and reliable than serum ferritin (20-22). However, 
this highly invasive technique, which carries significant risks of complication, is subject to 
considerable sampling error and bias, and is somewhat limited in the number of times it can be 
performed (23, 24). Consequently, it has fallen out of favor, especially for routine monitoring of 
iron loading in asymptomatic patients. For these reasons, annual surveillance with magnetic 
resonance imaging (MRI) has become the standard of care, especially for any patients on or 
transitioning to chronic transfusion therapy. The presence of iron alters the signal characteristics 
of effective T2 (T2*) sequences, where iron concentration leads to an inversely proportional 
shortening of relaxation. This shortening can be compared to established standards and from this, 


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LIC can be inferred. This technique has proven to be reliable, reproducible, and correlates well 
with traditional biopsy results (25, 26). The sequences can be obtained quickly, do not require 
contrast, and can even include measurements of cardiac and pancreatic iron. Thus, with increasing 
access to MRI, have replaced biopsy in most clinical settings, even in relatively resource-poor 
settings (27-29). It also has proven to be a useful tool in the research setting, monitoring the 
impacts of various treatments upon iron loading (30, 31).
Chelation therapy has proven revolutionary in the management of transfusion-dependent 
anemias including DBA, greatly reducing morbidity from the disease. Oral chelation agents 
(deferiprone and deferasirox) have also proven efficacious, while improving quality of life through 
ease of administration. However, in addition to the difficulties of adding yet another layer to the 
management of the disease, these agents also carry risks themselves. The most clinically 
significant complication is the potentially fatal agranulocytosis associated with deferiprone 
reported in several DBA cases and leading to an FDA black-box label (32, 33). Nonetheless, all of 
the chelation agents carry risks including sensorineural hearing loss and retinopathy, requiring 
additional clinical vigilance.
Despite these significant, well-studied complications, alternatives to chronic steroids and 
transfusion therapy have proven elusive. Therapies such as cytokines or immunomodulation have 
not proven effective and have significant side effects. Responses with second-line 
immunomodulatory agents used in other diseases such as aplastic anemia are rare. Ultimately, the 
only truly curative therapy is hematopoietic stem cell transplant. Although ongoing research into 
alternative donor transplants, graft-versus-host prophylaxis, and reduced-intensity conditioning 
have reduced the morbidity and mortality of HSCT while increasing its availability to more 
patients, it remains a high-risk procedure, especially in the setting of iron overload seen in DBA. 
Alternative therapeutic modalities for the half of patients without a durable remission are greatly 
desired.
2.3.
Thrombopoietin and Hematopoiesis
Thrombopoietin (TPO) was purified, identified and cloned by several independent research 
groups in academia and industry in the mid-1990s, based on its activity as the primary factor 
stimulating maturation of megakaryocytes and platelet release, and its binding to TPOR. TPO is a 
glycoprotein class 1 hematopoietic cytokine, produced primarily in the liver.
Several lines of evidence support a pleiotropic role for TPO in hematopoiesis, beyond its role as 
the primary endogenous factor controlling platelet production from megakaryocytes.  TPOR is 
expressed and functional on primitive HSPCs (34). Animals and patients with genetic defects in 
either TPO or TPOR have significant reduction in HSPC numbers and activity, along with profound 
defects in platelet production (35, 36). In vitro expansion of functional and phenotypic HSPCs can 


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be stimulated by TPO, either alone or in combination with other cytokines. Furthermore, TPO has 
been shown to mobilize a primitive subset of CD34+ cells in cancer patients with normal 
hematopoiesis (37, 38). The control of TPO levels is complex, and involves TPOR occupancy, with 
levels generally inversely proportional to megakaryocyte mass. Recently, the Ashwell-Morell 
receptor has been shown to regulate the hepatic thrombopoietin production by removal of 
desialylated senile platelets (39).
A slightly modified form of recombinant TPO, termed megakaryocyte growth and development 
factor (MGDF), was in clinical development by Amgen in the late 1990s. It clearly stimulated 
platelet production in vivo in healthy control individuals and in patients on chemotherapy, but its 
development came to a halt when both normal volunteers receiving MDGF prior to donating 
platelets and cancer patients receiving MGDF following chemotherapy developed neutralizing 
antibodies after several cycles of MGDF dosing, which reacted not only to MGDF but also to 
endogenous TPO, causing profound persistent thrombocytopenia (40, 41). It was shown that 
MGDF was acting as an immunogen due to modification from endogenous TPO, with epitope 
spreading eventually resulting in autoimmune destruction of endogenous TPO.
As mentioned earlier, proinflammatory cytokines negatively impact HSPC stemness and thus 
contribute to pancytopenia in bone marrow failure syndromes and potentially FA. Interferon 
gamma (IFN-γ) reduces proliferation but accelerates differentiation of progenitor cells. However, 
differentiation is skewed toward myelopoiesis at the expense of erythropoiesis. This effect 
appears to be associated with upregulation of key hematopoietic transcription factors. Inhibition 
of TPO signaling (e.g. STAT5) by the suppressor of cytokine signaling (SOCS) results in reduced 
self-renewal and proliferation of HSPCs in patients with BM failure (42). Interestingly, TPO has 
also been shown recently to improve the DNA-damage response in HSPC by increasing DNA-PK 
dependent nonhomologous end-joining efficiency (43, 44).
2.4.
Eltrombopag
Eltrombopag (SB-497115-GR, Promacta®), the bis-monoethanolamine salt form, is an orally 
bioavailable, small molecule 2nd generation thrombopoietin receptor (TPOR) agonist, developed 
for the treatment of thrombocytopenia by scientists at GlaxoSmithKline (now Novartis) (45). 
Studies conducted in vitro have shown that eltrombopag is an effective agonist binding to TPOR, 
the TPO receptor encoded by the MPL gene, to stimulate thrombopoiesis. It binds TPOR at a 
position distinct from the ligand binding site, within the juxtamembrane domain of the receptor, 
and thus does not compete with TPO for binding to its receptor (46). The differences in binding to 
the receptor may theoretically result in activation of different signaling pathways from native TPO, 
however, data indicate similar impact on megakaryocytes and stem cells comparing EPAG to TPO 
(47).


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In vivo, EPAG increased platelet numbers in chimpanzees (the only non-human species which is 
pharmacologically responsive to eltrombopag) (47). These findings, coupled with supporting 
clinical efficacy data in humans, suggested that eltrombopag is an orally active TPO-R agonist that 
functions in a similar manner to endogenous TPO. Initial clinical trials were carried out in normal 
volunteers, and then in patients with chronic ITP, based on their inappropriately low or low-
normal levels of endogenous TPO (48). The initial phase I/II and randomized, controlled phase 3 
registration trials in chronic ITP were very encouraging, with little toxicity and much higher 
responses in comparison with placebo (49-51), which led to its approval by the Food and Drug 
Administration (FDA) on November 20, 2008 for patients with chronic ITP who have had an 
insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag was the 
first oral TPO-R agonist approved for adult patients with chronic ITP. In November 2012, FDA 
approval was received for hepatitis C associated thrombocytopenia.
In analogy to TPO, EPAG appears to stimulate HSC proliferation and self-renewal, and was thus 
utilized by our group in a clinical trial for patients with refractory acquired SAA and shown to 
result in clinically-meaningful responses in about 50% (52, 53). Furthermore, the fact that the 
responses were sustained even after EPAG was discontinued supports its direct effect on the stem 
cell compartment in SAA patients. Based on these results in patients with SAA, EPAG was FDA 
approved for refractory SAA in August 2014, at an adult dose of 150 mg/day, higher than the doses 
utilized in ITP (52, 53). TPO levels are already markedly elevated in SAA patients, suggesting 
additional mechanisms leading to HSC expansion with EPAG treatment. Although EPAG’s function 
appears to be dependent on TPOR, it may activate the receptor differently than endogenous TPO 
(54-56). The different activation may result in the activation of distinct pathways favoring HSC 
fitness. Indeed, differences in signaling pathways between TPO and eltrombopag have been 
observed in platelets (47). In addition, our recent investigations indicate that EPAG can bypass the 
inhibitory effect of IFN-γ on TPOR signaling (57).
Longer follow-up in the ITP EXTEND trial (NCT00351468) suggests that eltrombopag remains 
well tolerated. On December 6, 2011 Novartis announced that the FDA agreed to modify 
eltrombopag’s Risk Evaluation and Mitigation Services designed to assure safe use of the novel 
agent and removed the requirement for healthcare professionals and institutions to enroll in the 
Promacta Care Program (Promacta® Package Insert, 2011). Monitoring of adverse events for 
eltrombopag will be continued via post-marketing surveillance programs and ongoing clinical 
trials, rather than a formal prescriber enrollment program. There has been no suggestion of an 
increased risk of myelodysplasia or any other clonal bone marrow disorder in patients treated on 
the EXTEND Trial for ITP.
2.4.1.
Rationale for eltrombopag in DBA
In a recent trial of eltrombopag (EPAG) for moderate aplastic anemia or hypoproliferative 


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unilineage cytopenias (NCT01328587, 11-H-0134), it was with great interest that we 
identified a patient with a clinical phenotype consistent with DBA and a de novo mutation 
in RPS19 who demonstrated a robust response to EPAG despite being refractory to prior 
therapeutic modalities (58). This response has been stable over three years of treatment 
but requires continuous EPAG to maintain transfusion independence (Figure 1). Our 
experience has led us to further examine the mechanism of TPO and TPO-independent 
pathways in treating DBA.
Figure 1: Hematologic response of a DBA patient to eltrombopag therapy. (A) Untransfused 
hemoglobin (red), (B) absolute neutrophil count (orange), (C) platelets (purple), and (D) ferritin 
(black) are plotted as a function of time from study enrollment. Periods of treatment with 
eltrombopag are indicated by the blue shaded areas, with height indicating dose (range 25-300 mg 
daily). Treatment had been discontinued after 10 months upon reaching endpoint goals, but was 
restarted at 17 months when counts fell below threshold, and has since been titrated according to 
hematologic response. (58)
2.4.1. Eltrombopag improves trilineage hematopoiesis in a TPOR-independent manner
0
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EPAG
A
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The trilineage response of patients to EPAG, despite the drug being an agonist directed 
primary towards the megakaryocytic lineage, suggests that EPAG may have multiple effects 
in vivo. Work by Kao et al. is of particular note as they demonstrated that EPAG is capable 
of stimulating hematopoietic stem cells in mice (59). This is notable because prior work has 
clearly demonstrated that the mouse receptor does not bind EPAG. Furthermore, 
romiplostim, an unrelated TPOR agonist, does not have this effect in mice. These results are 
suggestive of an EPAG-specific mechanism, independent of the TPOR found on 
megakaryocytes and primitive stem cells. For example, recent work by Guenther et al. has 
suggested that EPAG may improve hematopoiesis by improving the DNA damage response 
in hematopoietic cells (60). Others have examined the interaction of EPAG with the 
inflammatory milieu (57).
2.4.2.
Eltrombopag has clinically significant iron chelation activity in vivo
However, it is the iron-binding capabilities of EPAG that present the most promise for DBA 
patients, and likely explain the effects seen in our patient. Our work with EPAG has shown 
that it is capable of mobilizing intracellular iron and acting as a potent chelator, with 
patients on EPAG long-term dropping levels of storage iron over time (61). Indeed, EPAG 
has demonstrated a higher affinity for iron than clinically available chelators (62, 63). EPAG 
can mobilize iron from multiple different cell types at clinically relevant concentrations. 
Notably, EPAG can mobilize bone marrow iron observed in transfusion-related iron 
overload (64). Both orally available chelators (deferasirox and deferiprone) are also able 
to penetrate the cellular membrane due to their smaller size and chemical properties unlike 
deferoxamine (65-68). As such these agents are believed to have some intracellular 
chelation activity, especially within the heart, but this activity is highly variable, tissue-
dependent, and secondary to their main mechanism of action (69, 70). Indeed, continuous 
infusion deferoxamine remains the highly effective gold standard in the treatment of 
cardiac hemochromatosis despite its lack intracellular activity. These different agents are 
reviewed in (71). Therefore, a more potent intracellular chelator could have significant 
clinical impact.
Our own experiences with EPAG have confirmed that it is a potent chelator of iron and can 
mobilize whole body iron stores even in transfusionally iron-overloaded patients (61). 
Specifically, in patients on EPAG for at least 4 months, whole body iron as measured by 
serum ferritin was decreased, especially in patients treated on an extended access protocol 
(Figure 2), including our index DBA patient (Figure 1D). Paradoxically, in patients being 
treated with EPAG, serum iron levels are actually elevated, reflecting the mobilization of 
the intracellular iron into the blood stream, from which it is ultimately cleared and lost via 
hepatic processing of the iron-bound drug. Indeed, in several patients treated on extended 
doses of EPAG (average 2 years of drug exposure), iron supplementation was required due 


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to the development of iron deficiency anemia in the face of an otherwise strong response 
to EPAG. Several investigations into the metabolic effects of EPAG in cells have 
demonstrated that through the depletion of iron, there is a concomitant reduction in the 
toxic reactive oxygen species (59, 63, 72, 73).
Figure 2: Impact of eltrombopag upon iron stores in patients treated for aplastic anemia. 
(A) Ferritin levels in patients with EPAG treatment for at least 4 months. (B) Comparison of ferritin 
levels pretreatment and after EPAG discontinuation in 6 patients with prolonged EPAG treatment 
and ferritin measurements available at follow-up. Student’s t test: **P = .005 (61)
Given these findings of intracellular iron depletion, improvement in reactive oxygen 
species levels, and the clinical response we have previously seen in our DBA patient, we 
hypothesize that through its iron chelating properties, likely in combination with its 
stimulatory effects upon TPOR, EPAG may be able to offset the toxic effects of aberrant 
hemoglobin biosynthesis in DBA patients, increasing erythroid production, and ultimately 
allowing HSC self-renewal, thus improving anemia, preventing the long-term hematologic 
consequences of DBA, and even avoid the significant toxicities of transplant. By chelating 
and subsequently removing total body iron effectively, we hypothesize that EPAG will also 
improve organ function and overall long-term outcomes in DBA patients previously 
experiencing iron overload as a consequence of prior transfusion therapy.
2.4.3.
Rationale for dose selection
Eltrombopag 150 mg once daily in adults or the equivalent in children has been selected as 
the starting dose for this study because this dose regimen has been safe and effective in 
increasing platelet counts in our recently-completed non-randomized, off label, phase II 
study (NCT00922883) of EPAG as a single agent in patients with refractory SAA. Forty-
three (43) patients (age range 18-77 years) received 50 mg daily of EPAG with dose 
escalation every two weeks to a maximum dose of 150 mg daily. Patients were successfully 
escalated to the 150mg daily dose without dose-limiting toxicities. Hematologic responses 
A
B


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were only observed while patients were receiving the 150mg daily dosing. While it is 
possible that patients would have responded to lower doses of drug had the dose not been 
escalated every two weeks, the lack of toxicity at the 150 mg/day dose in the prior study 
supports our rationale for utilizing this dose throughout the current trial, unless dose 
modifications based on toxicity or response criteria are required.  A starting dose of 75 mg 
once daily in East Asian and South East Asian patients will be used. Modified dosing for 
subjects of East Asian and South East Asian heritage (self-reported) has been implemented 
for the following reasons. In healthy Japanese subjects, plasma eltrombopag AUC(0-) was 
approximately 80% higher when compared with non-Japanese healthy subjects who were 
predominantly Caucasian. Similarly, in patients with ITP, plasma EPAG levels were 
approximately 70% higher in East Asian and South East Asian subjects as compared with 
non–East Asian subjects who were predominantly Caucasian as higher drug exposure in 
East Asian and South East Asian subjects has been observed.
The most extensive data on dosing and long-term side effects have been obtained in 
patients with chronic ITP. An initial randomized phase 2 trial, followed by two randomized 
phase 3 trials all showed efficacy for EPAG compared with placebo for increasing the 
platelet count utilizing doses of up to 75 mg per day (49, 50, 74). In ITP subjects, there was 
a dose response for EPAG 30 mg to 75 mg once daily, with geometric mean AUC(0-) values 
of 169 g/mL for the 75 mg once daily regimen. There was no significant difference 
between the safety profile of ITP subjects receiving 30, 50 or 75 mg of EPAG. A recent 
update of the EXTEND study reported on 302 patients followed up to 5.5 years on EPAG 
therapy for chronic ITP, with a median exposure of 121 weeks and median dosing of 51.4 
mg/day. Forty-three (43) patients (14%) discontinued therapy due to adverse events, 
including headaches, thromboembolic events, or hepatobiliary laboratory abnormalities. 
An independent central pathology review of bone marrow biopsies did not reveal 
significant increase in reticulin deposition.
Thrombocytosis is a theoretical risk of EPAG treatment when high dosages are 
administered. However, thrombocytosis has not been observed in the 43 patients with 
refractory SAA who were treated with 150 mg per day nor in any of our other EPAG 
protocols (09-H-0199, 11-H-0134, 12-H-0150 and 13-H-0133). Thrombocytosis has been 
observed in healthy volunteers as well as in subjects with ITP, and there was a suggestion 
of a higher risk of thrombosis in patients on EPAG compared with placebo in the phase III 
randomized trials for chronic ITP(50). However, patients with ITP, in contrast to patients 
with DBA, have hyper-reactive platelets and an increased endogenous risk of thrombosis. 
In an extensive analysis of ITP patients treated long-term with romiplostim, an alternative 
TPO mimetic, there was no evidence for increased thrombotic events in the romiplostim-
treated patients compared with controls (75). In a meta-analysis of randomized trials using 
either EPAG or romiplostim, there was a numerically but non-statistically significant trend 


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to increased occurrence of thromboembolisms compared with controls (76). In the current 
trial, based on concerns regarding thrombosis, dose reductions of EPAG will be made if the 
platelet count reaches 600,000/µL or greater.
2.4.4.
Rationale for pediatric dose selection
For pediatric subjects, there is a predicted higher weight-adjusted drug clearance than 
older children and adults based upon studies of several drugs approved for use in children, 
such as anticonvulsants, proton pump inhibitors, theophylline, and HIV protease inhibitors, 
have routinely demonstrated that young children have higher weight-adjusted drug 
clearance than older children and adults (77-81).  In the PETIT trial, a phase II pediatric 
chronic ITP study, subjects between 1 and 5 years received a mean average daily dose of 
2.2 mg/kg EPAG (mean max 2.9mg/kg), while subjects between 6 and 11 years of age 
received an average daily dose of 54.8 mg daily while subjects aged 12-17 year received 
57.3mg EPAG. The maximum dose used in the PETIT trial among all age groups is 75 mg 
daily. Non-Asian patients aged 1-5 years, that were treated in the subsequent randomized, 
multicenter, placebo-controlled study PETIT2, started with 1.2 mg/kg/day. The median 
average dose per day was 3.4mg/kg (42.8 mg) in this cohort and 56.9mg/kg in patients 
aged 6-11 years. Non-East Asian patients aged 12-17 years were treated with a median 
average dose per day of 69.0 mg. No new pediatric specific safety signal has been identified 
thus far.
An analysis of combined pharmacokinetic data from the PETIT and PETIT2 trials, 
encompassing 168 pediatric patients with ITP aged 1 year and older, demonstrated that 
clearance increases with body weight. Notably, patients in the 1-5 year age group 
experience approximately 60% higher exposure to drug (AUC(0-) 162 µg·hr/mL 95% CI: 
139-187; Cmax 11.6 µg/mL 95% CI: 10.4-12.9) compared with adults (AUC(0-) 
101 µg·hr/mL 95% CI: 91.4-113; Cmax 7.03 µg/mL 95% CI: 6.44-7.68); whereas teenagers, 
aged 12 to 17 years, experience exposure (AUC(0-) 103 µg·hr/mL 95% CI: 91.1-116; Cmax 
6.80 µg/mL 95% CI: 6.17-7.50) comparable to adults. Older children and pre-adolescents, 
aged 6 to 11 years, experience an intermediate exposure (AUC(0-) 153 µg·hr/mL 95% CI: 
137-170; Cmax 10.3 µg/mL 95% CI: 9.42-11.2) that is nonetheless similar to toddlers and 
young children (82).
The available platelet count, safety, and PK data available for subjects enrolled in the PETIT 
trial support a starting dose of 2.5 mg/kg once daily for non-East-Asian subjects aged 2-5 
years (82-84). Older pediatric patients will start at a fixed total dose; however, as they are 
expected to experience a higher pharmacologic exposure compared to adults, the starting 
dose for non-East-Asian subjects, aged 6-11, will be 75 mg daily. Patients 12 years and older 
will start at the adult dose of 150 mg daily.


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2.4.5.
Rationale for permitting dose interruption
The effect of dose interruption is unknown in the DBA population. Thirty-one percent (34 
ITP subjects) on the long-term extension study (EXTEND Trial, NCT00351468) had an 
interruption to EPAG dosing at some point in the study.  Of the subjects requiring a dose 
interruption, 7 had a dose interruption lasting 1 to 7 days and 27 had a dose interruption 
lasting greater than 7 days.  Platelet counts decreased back to baseline within 1-2 weeks, 
although not associated with any bleeding complications. However, the underlying 
pathophysiology of thrombocytopenia in ITP is very different from DBA or SAA, and EPAG 
is being utilized in that disorder to overproduce platelets in the bone marrow to 
compensate for increased and ongoing antibody-mediated platelet destruction. In DBA, we 
postulate an effect on HSCs in the bone marrow, and a much more prolonged effect from 
EPAG; therefore, our prediction would be that short or even longer-term dose interruptions 
will not result in any sudden changes in blood counts. We would anticipate some patients 
on the current trial might have dose interruptions due to intervening illnesses such as 
gastroenteritis, and may require suspension of the study drug temporarily.
2.4.6.
Rationale for treatment duration (primary endpoint 6 month), extended access to 
EPAG for responding patients and slow tapering of EPAG during this extension 
part of the study
Eltrombopag is safe and relatively non-toxic with prolonged use. The EXTEND study 
(NCT00351468), an open label dose modification extension study evaluating the safety and 
efficacy of extended therapy of EPAG in ITP subjects, has been designed to assess long-term 
effects of EPAG therapy. At the most recent analysis of 302 patients (presented at EHA, 
2016) the median average daily dose was 50.4 mg. The median duration of exposure to 
EPAG was 2.4 years (range, 2 days to 8.8 years). EPAG was well-tolerated, and both 
bleeding and clinically-significant bleeding decreased from baseline at all time points. AEs 
and SAEs occurred in 92% and 32% of patients respectively. SAEs considered possibly 
drug-related occurred in 8% of patients. AEs leading to withdrawal occurred in 14% of 
patients. The most frequent AEs leading to withdrawal were increased ALT (n=5), 
increased bilirubin (n=4), cataracts (n=4), and DVT (n=3). Nineteen patients (6%) reported 
thromboembolic events (TEEs), and 37 reported hepatobiliary laboratory abnormalities. 
ITP patients have return of their platelet counts to baseline within 1-2 weeks of 
discontinuation of drug.
In our cohort of 43 patients treated for refractory severe aplastic anemia (SAA), responses 
only began to be observed at the 3-month time point, and with continued exposure to drug, 
blood counts of all lineages improved towards the normal range gradually. Maximal 
response was not reached at 6 months with bone marrow cellularity normalizing by 9-15 


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months. Eighteen of 43 patients with refractory SAA had drug discontinued for robust 
response. Only 2 patients showed a decrease in counts clearly related to the 
discontinuation of EPAG. Re-initiation of EPAG restored hematopoiesis in both patients. 
However, EPAG was discontinued in one patient because of an intermittently detected 
cytogenetic abnormality. Since then the counts have remained stable and a repeat bone 
marrow biopsy showed a normal karyotype. These results suggest that the effect of EPAG 
on HSPC number or function is long-lasting and prolonged therapy may not be required in 
SAA.
In patients with DBA the HSPC potential is also reduced but, unlike acquired BMFS, HSPC 
in subjects with DBA carry inherited mutations impacting hemoglobin synthesis (§2.1). 
Assuming no increased rates of spontaneous somatic reversion of inherited mutations, a 
rare but reported event (85-88), resulting in a selective growth advantage of corrected 
HSCs, hematopoiesis in patients with DBA will continue to rely on HSPC with the underlying 
genetic defect. Therefore, it is likely that patients with DBA will require continuing or 
repeated EPAG treatments to improve their anemia. Yet, the lowest dose and shortest 
exposure able to improve cytopenias into a safe range would be the goal for EPAG therapy 
in this patient population. Based on the response kinetic of our previous (52, 53) and 
ongoing EPAG studies in patients with refractory aplastic anemia (13-H-0133, 
NCT01891994), we hypothesize that 6 months of EPAG treatment will be sufficient to 
assess for a clinically meaningful response also in DBA patients.
Thus, in this study, to determine the lowest optimal dose of EPAG in patients responding to 
the drug, we plan a slow taper of EPAG in robust responders or subjects who reach steady 
state response defined as stable counts for 6 months (see §5.3, Table 3). Toxicity and 
efficacy data will continue to be collected during that time to help identify the secondary 
endpoints of duration of response, progression to clonal hematopoiesis, and toxicities with 
extended duration of therapy.
2.5.
Scientific and clinical justification of the protocol
Without treatment, DBA progresses to critical anemia in over four-fifths of all cases. Even with 
treatment, approximately half of patients will either fail to respond, do not have a durable 
response, or are unable to continue therapy due to steroid-associated toxicities. For these patients, 
chronic transfusions with the risk of cardiovascular, hepatic, endocrinologic, and other systemic 
organ dysfunction and a major impact on quality of life is the only management option with proven 
benefit. Yet, even with chelation therapy, due to long-term toxicities of chelators and iron loading, 
coupled with the effects of chronic anemia upon growth and development, cardiovascular health, 
and neurodevelopment, leads to a reduced life expectancy in DBA. HSCT remains the only 
definitive treatment for the hematologic complications of DBA. Yet, despite significant advances in 


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preparative regimens, supportive care, and management of complications, HSCT continues to 
carry significant morbidity and mortality, especially in the heavily pre-transfused population. In 
addition, many patients do not have available and sufficiently-matched related or unrelated 
donors. As a result of these complications of the disease and a paucity of effective alternative 
treatments, novel treatments for patients with DBA are acutely needed.
As discussed above (§2.1), DBA represents a spectrum of diseases caused by a variety of mutations 
in at least 21 genes affecting multiple different cellular pathways, but all converging on an excess 
of iron-containing heme pigment within the erythroid progenitors leading to iron accumulation 
and subsequently toxic levels of reactive oxygen species. With time, the accumulation of toxic 
intracellular and extracellular species causes a general bone marrow failure, leading to 
progressive cytopenias and bone marrow failure. Additionally, the chronic transfusions used to 
treat the most-affected of these patients further increases the marrow iron loading, exacerbating 
the cellular damage in addition to the non-hematologic complications of therapy.
Eltrombopag, in addition to stimulating the proliferation and differentiation of hematopoietic 
lineages, is a potent chelator of intracellular and extracellular iron, with activity demonstrated 
both in vitro and in vivo (§2.4.2). We hypothesize that this iron-depleting activity reduces the 
intracellular iron burden and thus the oxidative stresses upon the progenitor cells, thus leading to 
the clinical response we have seen in our single previously-treated DBA patient (§2.4.1). 
Therefore, based upon safety evidence provided by  prior clinical trials and efficacy suggested by 
pre-clinical data and our clinical experience, we propose this study to demonstrate that by 
targeting the common pathway of DBA, this effect should be generalizable to all DBA patients and 
thus provide a novel treatment paradigm for DBA that will reduce or eliminate the transfusion 
burden and steroid side effects that plague DBA patients.
DBA, as noted above, is a cancer-predisposition syndrome (§2.2) including both solid tumors and 
hematologic malignancies. Although the biology of this predisposition is poorly understood, it 
likely represents genotoxic stress from the same toxic processes that lead to erythroid aplasia. In 
the marrow, the combined hematopoietic stresses of ineffective hematopoiesis, ongoing cellular 
damage leading to cytopenias and likely driving clonal progression, oxidative stress of free heme, 
and increased total body iron burden, especially within the marrow compartment, predisposes to 
dysplasia and malignant transformation. Although beyond the immediate scope of this trial, we 
hypothesize that by reducing these combined stresses, EPAG treatment will reduce the risk of 
hematopoietic and even non-hematologic malignancies in DBA. Furthermore, by reducing the 
need for HSCT, EPAG may have the secondary effect of reducing the risk of treatment-related 
morbidity, malignancies, and mortality.
The primary objective of this trial will be to evaluate the safety and efficacy of eltrombopag as a 
single agent in subjects with Diamond-Blackfan anemia, especially patients with relapsed disease, 


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refractory disease, or patients who cannot tolerate ongoing standard therapies. The secondary 
objectives of this trial will include assessments of the impact of eltrombopag upon rates of relapse 
and survival, clonal evolution, toxicities of extended therapy, the impact of treatment upon health-
related quality of life and neurodevelopment in pediatric patients, and the impact of eltrombopag 
upon stem cell and erythroid cell dynamics and niche interactions including iron homeostasis.
3. Study Design
The study is designed as a single-site, non-randomized, single-arm pilot study of the oral TPOR 
agonist eltrombopag (EPAG) in Diamond-Blackfan anemia (Figure 3) to test the hypothesis: 
eltrombopag improves the production of red blood cells in Diamond-Blackfan anemia 
patients. The primary endpoint (see §8.2) is measured at 6 months (24 weeks ± 14 days). Subjects 
who cannot tolerate the medication or fail to respond by the primary endpoint will be taken off 
study drug. Subjects who respond at the primary endpoint (hemoglobin increase of 1.5 g/dL or 
more and/or transfusion independence for the previous 8 weeks, see §8.2.1) will be able to 
continue EPAG on the extension part of this protocol for an additional 3 years. During the 3-year 
extension phase, subjects will remain on the same dose of EPAG until they reach a robust response 
(defined as hemoglobin ≥10 g/dL in the absence of transfusions for more than 8 weeks, see §8.2.1). 
Drug dose will then be tapered slowly to the lowest dosage that maintains a stable hemoglobin 
(≥ 10 g/dL) and eventually discontinued if possible (per §5.3), until they meet off study criteria 
(see §8.6), or the study is closed. Drug will be restarted during extension if robust response is lost 
(i.e. hemoglobin falls below 9 g/dL).
Up to 30 subjects (18 for Stage 1 & 12 for Stage 2) will be screened to accrue 25 eligible subjects 
for this study.
Figure 3: Study enrollment and treatment schema
Stage 1: 18 DBA patients
Stage 2: 12 DBA patients
See §8.3
ENROLLMENT
INTERIM ASSESSMENT
PRIMARY ENDPOINT
Weeks 0-12
Weeks 12-24
OFF-STUDY
Up to 3 years
Bi-weekly 
Laboratory 
assessments
Bi-weekly 
Laboratory 
assessments
RESPONSE
NON-RESPONSE
Extension: Dose taper
See §5.3
Eltrombopag: 150 mg/day starting dose
Titration and adjustments for age and ethnicity per §5


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4. Eligibility Assessment
4.1.
Inclusion criteria
In order to be participate in this study, individuals must meet all of the following criteria:
4.1.1.
Diamond-Blackfan anemia defined as anemia presenting on or before the third 
year of life with reticulocytopenia and greatly reduced or absent bone marrow 
erythroid precursors, supported by, but not requiring either:

familial history

gene mutation testing demonstrating a known disease-causing mutation or 
a mutation of disease-associated gene in combination with clinical 
characteristics of DBA
Patients with late-onset DBA (diagnosed after the third year of life) may also be 
included if gene mutation testing confirms a disease-causing mutation as above. 
4.1.2.
Clinically-significant anemia as defined as either:

hemoglobin less than 9.0 g/dL

red cell transfusion of at least 2 units PRBC for adults or 30 cc/kg for children 
(whichever is less) in the eight weeks prior to study enrollment
4.1.3.
Relapsed and/or steroid-refractory or intolerant of systemic corticosteroids
4.1.4.
Age ≥ 2 years
4.1.5.
Weight ≥ 12 kilograms
4.1.6.
Residence within the United States of America or territories, or able to reside 
within the US or its territories while on drug during trial participation
4.2.
Exclusion criteria
Individuals meeting any of the following criteria will not be eligible for participation in this study. 
However, having met exclusion criteria in the past does not preclude study participation if the 
criteria are no longer met, unless otherwise specified (i.e. patients with modifiable factors such as 
laboratory abnormalities or acute health problems may be re-screened). For laboratory 
assessments, this requires no less than two weeks from the previous exclusionary finding. The 
intervals for health problems that must elapse prior to re-screening are specified below.
4.2.1.
Platelet count > 400,000 / µL


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4.2.2.
Stage 4 or greater kidney disease as defined by creatinine > 2.5 mg/ dL or GFR 
< 30 mL/min/1.73 m2
4.2.2.1.
For pediatric patients 17-years-old or younger, GFR shall be used. 
This can be estimated using the bedside Schwartz equation, the Counahan-
Barratt method, or a similar methodology. Direct measurement including, 
but not limited to, 24-hour urine creatinine clearance or radiographic 
methods is recommended for patients with stage 3 disease (GFR ≤ 45 
mL/min/1.73 m2).
4.2.3.
Direct bilirubin > 2.0 mg/ dL, including congenital abnormalities in the bilirubin 
level
4.2.4.
SGOT (AST) or SGPT (ALT) > 5 times the upper limit of normal
4.2.5.
Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 
4 weeks prior to initiating eltrombopag.
4.2.5.1.
Physiologic steroid replacement for adrenal insufficiency or other 
similar conditions is not exclusive of trial participation
4.2.6.
Treatment with any medications that may interfere with the metabolism of 
eltrombopag (e.g., CYP1A2 and CYP2C8 modulators) or whose own altered 
metabolism by eltrombopag cannot be adjusted for (see §5.8, 5.9, and 10.3.1)
4.2.7.
Hypersensitivity to eltrombopag or its components
4.2.8.
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
4.2.9.
Life expectancy of less than 3 months for any cause
4.2.10.
Subjects with known liver cirrhosis in severity that would preclude tolerability of 
eltrombopag as evidenced by albumin < 3.5g/dL
4.2.11.
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,


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
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

Impaired cardiac function such as corrected QTc>450msec using Fridericia 
correction on the screening EKG, other clinically significant cardio-vascular 
disease (e.g. uncontrolled hypertension, history of labile hypertension), 
history of known structural abnormalities (e.g. cardiomyopathy).
4.2.12.
Known active or uncontrolled infections not adequately responding to 
appropriate therapy.
4.2.12.1.
HIV infection is not exclusive of trial participation if the infection is 
effectively controlled with medications not known to interfere with 
eltrombopag metabolism or be metabolized by pathways known to be 
altered by eltrombopag (as per §4.2.6). HIV RNA viral load must be 
undetectable at the time of enrollment, and CD4 cell count must be 
≥ 200/µL. Patients must remain on antiretroviral therapy throughout study 
participation and must be periodically monitored for suppression of viral 
load and CD4 cell count. If drug-drug interactions between antiretroviral 
medications and eltrombopag are suspected, these must be addressed by a 
qualified clinical pharmacist or pharmacologist, and any changes to 
antiretroviral therapy need to be approved in consultation with an 
Infectious Disease and/or HIV specialist prior to enrollment.
4.2.13.
Active malignancy or likelihood of recurrence of malignancies within 12 months
4.2.14.
Evidence for MDS or AML as defined by WHO criteria.
4.2.15.
Patients who have received chemotherapeutic treatment or other specific 
antineoplastic drugs or radiation therapy within 6 months of study entry
4.2.16.
Female subjects who are nursing or pregnant (positive serum or urine β-human 
chorionic gonadotrophin (b-hCG) pregnancy test) at screening or pre-dose on 
Day 1.
4.2.17.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of 


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contraception during dosing and for 30 days after the last dose of eltrompobag. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of 
the patient. 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). For female patients 
on the study the vasectomized male partner should be the sole partner for 
that patient.

Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS), or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception.

In case of use of oral contraception women should have been stable on the 
same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential 
if they have had over 12 months of natural (spontaneous) amenorrhea with 
an appropriate clinical profile age appropriate (e.g. generally 40-59 years), 
history of vasomotor symptoms (e.g. hot flushes) in the absence of other 
medical justification or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level 
assessment should she be considered not of childbearing potential.
o
Sexually active males unless they use a condom during intercourse while 
taking the study treatment and for 30 days after stopping study 
treatment 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 seminal fluid.
4.2.18.
History of thromboembolic events other than catheter-related thromboses
4.2.19.
Active alcohol/drug abuse


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4.2.20.
Unable to understand the investigational nature of the study or give informed 
consent and does not have a legally authorized representative or surrogate that 
can provide informed consent
4.2.21.
Unable to take investigational drug
4.2.22.
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.
5. Treatment Plan
5.1.
Administration of study drug (eltrombopag)
Subjects will initiate EPAG at a starting daily dose as detailed below, according to age and ethnicity. 
Subjects 12 years of age and above will receive the adult dose of 150 mg. Those between 6 and 11 
will start at 75 mg, and children 2 and 5 years of age will start at 2.5 mg/kg, not to exceed 75 mg 
(Table 1).
To adjust for the higher expected exposure in subjects of East Asian and South East Asian ancestry, 
the starting dose for East Asian and South East Asian subjects 12 years of age and above will be 75 
mg once daily.  For East Asian and South East Asian subjects between 6 and 11 years of age, the 
starting dose will be 37.5 mg once daily, and for children between 2 and 5, the starting dose will 
be 1.25 mg/kg (Table 1).
Table 1: Starting daily dose of eltrombopag according to age and ethnicity
Age group
Daily dose
Non-Asian
≥12
150 mg
6-11
75 mg
2-5
2.5 mg/kg, max 75 mg
East Asian, South East Asian
≥12
75 mg
6-11
37.5 mg
2-5
1.25 mg/kg, max 37.5 mg
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. If EPAG dosing is delayed or interrupted for more than 1 week (7 days) and the 
interruption is not the result of a severe adverse event related to EPAG, then the subject will 
receive EPAG for additional time in order to receive a total of 24 weeks as originally planned. 
Interruptions shall be recorded in the medical record. Whether interruptions are reported (e.g. as 
deviations or adverse events) shall be determined as per Policy 801.


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Medication dosing errors, dose delays or dosing interruptions:
Interruptions such as delays in request for medication refills or medication errors by subjects, 
unless they result in a serious adverse event or impact the integrity of the research data, will not 
be considered as deviations, but will be recorded in the medical record.
5.2.
Dose adjustments of eltrombopag
Table 2: Criteria for the adjustment of the daily dose of eltrombopag
Platelet Count
Dose Adjustment or Response
≥400,000/µL (untransfused) at any 
time on study
Decrease dosage by 25 mg/day (or 12.5 mg in 
children under 12) every 2 weeks (± 3 days) to 
highest dosage that maintains hemoglobin 
≥9 g/dL without increasing platelet count 
≥400,000/µL. For subsequent elevations over 
400,000/µL, the dose may be reduced by up to 
50%.
≥600,000/µL (untransfused) at any 
time on study
Discontinue eltrombopag for one week (± 3 
days); when platelets fall to <400,000/µL, restart 
at dosage decreased by at least 25 mg/day (or 
12.5 mg in children under 12) or up to 50%.
5.3.
Taper of eltrombopag in the extension protocol
Once a robust blood count recovery occurs in the extension part (i.e. hemoglobin >10 g/dL in the 
absence of transfusions for more than 8 weeks), EPAG dose will be tapered according to Table 3. 
If hemoglobin falls to <9 g/dL or the patient again requires RBC transfusions then EPAG will be 
either re-initiated or the dose will be increased to the last effective strength.
Table 3: Eltrombopag taper in the extension protocol
Age group
Starting dose
Step 1
Step 2
Step3
Step 4
Non-Asian
≥12
150 mg
75
37.5
25
stop
6-11
75 mg
37.5
25
12.5
stop
2-5
2.5 mg/kg
1.25mg/kg
stop
East Asian, South East Asian
≥12
75 mg
37.5
25
12.5
stop
6-11
37.5 mg
25
12.5
stop
2-5
1.25 mg/kg
stop
Each step is 8 weeks


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5.4.
Dose delays, modifications or discontinuation 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 patient is stable.
5.4.2.
Liver function abnormalities
Recommended dose modifications for isolated ALT or AST elevation are listed in Table 4.
Table 4: Eltrombopag dose modifications for isolated ALT or AST elevation
Elevation
Dose modification and Follow-up
>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. 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, restart eltrombopag at a dose level 25mg/day 
(12.5mg/day for children under 12) lower than the prior dose. 
>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.
If resolved, restart eltrombopag at a dose level 25mg/day (12.5mg/day for 
children under 12) lower than the prior dose.
>20.0 x ULN
Discontinue subject from study drug treatment.
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 or stabilization over 4 weeks.


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5.5.
Dose delays, modifications or discontinuation for hematologic side effects
5.5.1.
Thrombosis/Embolism
Subjects who experience a deep venous thrombosis or a pulmonary embolus, transient 
ischemic attack or stroke, or a myocardial infarction at any time while on EPAG will 
discontinue drug and go off study. They will be treated for the thrombotic event as 
clinically-indicated.
5.5.2.
Peripheral blood smear shows new morphological abnormalities
The presence of persistent morphologic abnormalities (red cell teardrop forms or immature 
blasts) or the development of significant sudden worsening of platelet or neutrophil counts 
while on study will require discontinuation of EPAG and performance of a bone marrow 
examination to assess for development of abnormal fibrosis or progression to MDS or AML.
5.6.
Extended access to study drug
Subjects who demonstrate response by protocol criteria at 24 weeks (± 10 days) may be consented 
to continue EPAG on study. This part of the study will be referred to as extended access phase. Per 
dosing criteria given in §5.1, patients may remain on the extended access phase as long as they 
maintain a response. While on extended access, participants may have drug tapered, discontinued, 
and/or re-started as per §5.2, 5.3 and 5.4.
5.7.
Permitted supportive care

Transfusion supportive care (e.g., blood and platelets) as clinically indicated.

Iron chelation therapy (e.g. deferasirox, deferoxamine, deferiprone) ongoing at the time of 
enrollment will be continued, titrating and/or discontinuing according to established 
standards of care.

Estrogens or combination oral contraceptives as indicated for uterine bleeding.

Prophylactic antibiotics and antivirals as clinically indicated.

The PI should be informed about all medications initiated after starting treatment with 
EPAG.
5.8.
Non-permitted medications

Romiplostim (N-Plate)

IL-11 (Neumega)

Androgens (danazol and oxymetholone) within 4 weeks prior to starting EPAG.

Corticosteroids within 4 weeks prior to starting EPAG, except at physiologic replacement 
dosing for adrenal insufficiency


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
Investigational or not marketed drugs without a well-known safety profile within 7 days or 
5-half-lives (whichever is longer) prior to the first dose of study treatment and until 
eltrombopag is discontinued unless, in the opinion of the Investigator and Sponsor, the 
medication will not interfere with the study.

Herbal supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 
5-half-lives (whichever is longer) prior to the first dose of study treatment until 
eltrombopag is discontinued, unless in opinion of the Investigator and Sponsor, the 
medication will not interfere with the study treatment.
5.9.
Concurrent medications
OATP and BCRP substrates: In vitro studies demonstrated that eltrombopag is an inhibitor of 
the transporters OATP1B1 (Organic Anion Transporter Polypeptide-1B1) and BRCP (Breast 
Cancer Resistance Protein). Administration of eltrombopag 75 mg once daily for 5 days with a 
single 10 mg dose of rosuvastatin, an OATP1B1 and BCRP substrate, increased plasma 
rosuvastatin Cmax by 2-fold and AUC∞ by 55% on average. Interactions are also expected with other 
HMGCoA reductase inhibitors.
When co-administered with eltrombopag, a reduced dose of HMG-CoA reductase inhibitors should 
be considered, and careful monitoring should be undertaken. Concomitant administration of 
eltrombopag and other OATP1B1 and BCRP substrates should be undertaken with caution.
Examples of OATP substrates: aliskiren, ambrisentan, anacetrapib, atenolol, atrasentan, 
atorvastatin, bosentan, bromociptine, caspofungin, cerivastatin, celiprolol, danoprevir, 
empangliflozin, ezetimibe, fimasartan, fexofenadine, fluvastatin, glyburide, maraviroc, SN-
38 (irinotecan metabolite), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, 
repaglinide, rifampin, valsartan, olmesartan, telmisartan, montelukast, ticlopidine.
Examples of BCRP substrates: atorvastatin daunorubicin, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, pitavastatin, rosuvastatin, SN-38, ethinyl estradiol, 
simvastatin, sulfasalazine, sofosbuvir, topotecan, sulfasalazine.
Inhibitors of cytochrome p450: In vitro studies demonstrate that CYP1A2 and CYP2C8 are 
involved in the oxidative metabolism of EPAG. Trimethoprim, gemfibrozil, ciprofloxacin, 
fluvoxamine and other moderate or strong inhibitors of CYPs may therefore theoretically result in 
enhanced activity of EPAG, however these interactions have not yet been established in clinical 
studies. Subjects on cyclosporine requiring prophylaxis against PCP should be given inhaled 
pentamidine instead of TMP/SULF. NIH patients with bone marrow failures are routinely placed 
on pentamidine instead of TMP/SULF for PCP prophylaxis to avoid potential marrow-suppressive 
effects of TMP/SULF anyway. Other CYP inhibitors can be used concomitantly but with careful 
attention to possible increased EPAG activity and toxicity.


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HMG-CoA Reductase Inhibitors (statins): Patients will be permitted to use HMG-CoA reductase 
(3-hydroxy-3-methyl-glutaryl-CoA) inhibitors during the study, but these drugs should be used 
with caution and a 50% dose reduction of the HMG-CoA reductase inhibitor is recommended, with 
close monitoring for safety, such as liver chemistry and signs and symptoms of myolysis, and 
efficacy, such as cholesterol and triglycerides (refer to individual product information for 
monitoring recommendations).
5.10.
Instructions to patients
Timing in relation to food: Subjects will be advised to take EPAG on an empty stomach i.e. 1 hour 
before or 2 hours after a dairy-free meal containing no drugs, antacids, or products with polyvalent 
cations (i.e. aluminum, calcium, magnesium, iron, selenium and zinc) such as mineral supplements.  
For meals containing dairy products, patients will be advised to take EPAG at least 4 hours before 
or after meals.
Timing in relation to antacids and other products containing polyvalent cations: Because co-
administration of EPAG with antacids decreased plasma AUC of EPAG by 70%, patients will be 
advised to take EPAG at least 4 hours before or after from antacids and other products containing 
polyvalent cations such as mineral supplements and dairy products.
5.11.
Health Related Quality of Life (HRQL) Questionnaires
The relevant dimensions of HRQL being assessed in this study include (1) PROMIS Global Health, 
Sleep Disturbance, Applied Cognition-Abilities, Anxiety and Depression and (2) FACT- Anemia, 
Thrombocytopenia and Neutropenia. Patient-Reported Outcomes Measurement Information 
System (PROMIS®), is an initiative based on an NIH grant to establish and provide the public a 
free, reliable and validated commonly used measures of patient-reported outcomes. The FACT 
instruments are a health assessment instrument designed to measure multi-dimensional quality 
of life in chronic illness and its associated therapy. The different subscales selected for this study 
are specific for patients with diseases or treatments with hematological effects.
6. Clinical Evaluations
Samples will be ordered and tracked through CRIS.  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. For laboratory assessments, the following limits will be observed:
Adult Patients: The amount of blood that may be drawn from adult patients and volunteers (i.e. 
those persons 18 years of age or older) for research purposes shall not exceed 10.5 mL/kg or 550 
mL, whichever is smaller, over any eight-week period. The amount of blood to be drawn from 


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volunteers and the frequency of collection shall be specified in the clinical research protocol, and 
exceptions to the 10.5 mL/kg or 550 mL limitations shall be approved by the IRB.
Pediatric Patients: For pediatric patients, no more than 5 mL/kg may be drawn for research 
purposes in a single day, and no more than 9.5 mL/kg may be drawn over any eight-week period.
6.1.
Pre-study evaluation
Pre-study evaluations to determine eligibility and baseline status may be performed under an IRB 
approved protocol (for instance the screening protocol 97-H-0041, or studies such as bone 
marrows performed as follow-up on another NHLBI treatment trial) or as part of this protocol. 
Patients will be evaluated at the NIH within 12 weeks prior to signing consent. This evaluation 
includes a bone marrow aspiration and biopsy with cytogenetics to determine eligibility, and these 
results take up to two weeks to be reported. If a patient is not local, the labs listed below required 
to be performed within 7 days of signing consent can be performed by their home physician’s 
outside lab, and if they confirm continued eligibility, telephone consent can be obtained. All time 
frames listed below are relative to the day consent is signed for this protocol. The source of the 
pre-study and eligibility data will be appropriately documented.  The pre-study evaluations will 
include the following:

Medical history and physical examination

Concurrent medication review

Complete blood count with differential

Peripheral blood smear

Reticulocyte count

Hemoglobin F quantification by hemoglobin electrophoresis

Erythrocyte adenosine deaminase

DAT (direct antiglobulin test)

Chromosomal breakage analysis (if results not available from outside/referring institute)

Genetic testing (if results not available from outside/referring institute)
o
Targeted sequencing if a family history of DBA exists and the mutation is known
o
Inherited bone marrow failure panel (NeoGenomics “Inherited bone marrow failure 
panel”, University of Chicago “Hereditary Myeloid Malignancy and Inherited Bone 
Marrow Failure Panel”, Cincinnati Children’s Hospital “Bone Marrow Failure 
Syndromes Panel by next-generation sequencing”, or a comparable test 
encompassing known DBA genes)

Acute care panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)

Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin)

Total Protein, CK, Uric Acid, LDH

Mineral (Phosphorus, Magnesium, Albumin, and Calcium)


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
Coagulation and thrombosis screens (PT, PTT)

Viral serologies for hepatitis A, B, C, HIV, HSV, EBV and CMV (positive serologies will have 
viral nucleic acid testing performed)

Folate level

B12 level

Copper and zinc levels

Iron panel (ferritin, transferrin, % saturation, total serum iron)

Pregnancy test (blood or urine hCG in women of child bearing potential)

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, iron, 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

Pediatric consult for patients under 18 years of age

Electrocardiogram (EKG)

Review of red blood cell transfusion records for the 8 weeks prior to study entry
6.2.
Baseline labs
Laboratory evaluations performed as part of screening may be used if obtained within 7 days prior 
to consent. Screening results (§6.1) may be used as baseline studies if performed within 12 weeks 
or as indicted below. 

Complete blood count with differential (7 days or less prior to signing consent)

Reticulocyte count (7 days or less prior to signing consent)

Acute care panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) (7 days or less 
prior to signing consent)

Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin) 
(7 days or less prior to signing consent)

Pregnancy test (blood or urine hCG in women of childbearing potential) (7 days or less 
prior to signing consent)
The below baseline testing will be obtained once patient is consented onto study:

MRI T2* imaging to assess liver iron concentration

Neurodevelopmental testing for patients less than 18 years of age (recommended, but at 
PI’s discretion)

24-hour urine collection to determine the total iron (at PI’s discretion)

HLA typing


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
HRQL survey administration

Immunoglobulins

Thyroid function panel (T3, T4, and TSH)

Research blood as detailed in §7
6.3.
On-Study evaluations (through 6 months ± 10 days)
Subjects may be followed by their home physician or at the Clinical Center. Lab tests not done at 
the NIH will be faxed or securely e-mailed to the Research Nurse. The PI will review outside test 
results and these will be uploaded into CRIS, and all lab data will be recorded. Any progress notes 
from local assessments will be faxed or securely e-mailed to the research nurse and reviewed by 
the principal investigator.

Complete blood counts with differential (every 2 weeks ± 10 days)

ALT, AST, Total Bilirubin or Direct Bilirubin (every 2 weeks ± 10 days)

Ferritin (every 2 weeks ± 10 days)

Full iron panel (transferrin, % saturation, and total serum iron) in addition to ferritin 
preferred but not required
6.4.
Landmark 3-month and 6-month evaluations
Subjects must be evaluated at the 3- and 6-month (± 14 days) time points. The 6-month time point 
shall be at the NIH Clinical Center. The 3-month assessment may be either at a home institution or 
at the NIH.

Review of interval history and events

Physical exam (may be omitted for 3-month evaluation if visit is not at the NIH)

Complete blood counts with differential

Acute care panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)

Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium)

Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin)

Other (Total Protein, CK, Uric Acid, and LDH) panel

Reticulocyte count

Iron panel (ferritin, transferrin, % saturation, total serum iron)

Blood or urine pregnancy test (woman of childbearing potential only)

Review of transfusion records (if available)
Additional assessments to be obtained at the NIH Clinical Center at the 6-month evaluation:

Neurodevelopmental assessment for patients less than 18 years of age (if previously 
performed)


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
Peripheral blood smear

Hemoglobin F quantification by hemoglobin electrophoresis

Erythrocyte adenosine deaminase

Copper and zinc levels

MRI T2* imaging to assess liver iron concentration

24-hour urine collection to determine the total iron content at PI’s discretion if indicated 
for iron metabolism and excretion studies

Blood for pharmacokinetic evaluation of EPAG levels at PI’s discretion. Samples drawn pre-
dose, and at 2-, 4-, 6- and 8-hour post-dose timepoints, with an optional final sample at 24 
hours after dose

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

HRQL survey administration

Research blood as detailed in §7
6.5.
Long term follow-up for responding patients enrolled in extended access phase
Patients fulfilling response criteria (per §8.2) at the 6-month visit will be offered participation in 
the extended access phase and after signing consent will be permitted to continue on EPAG for an 
additional 3 years. Subjects taking EPAG must be evaluated at the Clinical Center every 6 months 
(± 30 days) while they remain on extended access and continue periodic laboratory monitoring 
listed below in their home physician’s office or the NIH every 4 weeks (± 10 days). Progress notes 
and lab tests not done in NIH will be faxed or securely e-mailed to the Research Nurse. The PI will 
review outside test results and these will be uploaded into CRIS and filed in the research charts, 
and all lab data will be recorded. The periodic laboratory monitoring will include:

Complete blood counts with differential (every 4 weeks (± 10 days).

Reticulocyte count every 4 weeks (± 10 days).

ALT, AST, Total Bilirubin or Direct Bilirubin every 4 weeks (± 10 days).

Ferritin every 4 weeks (± 10 days).
6.5.1.
Testing required for patients on EPAG while on extended access EPAG (up to 3 
years after the 6-month visit):

Complete blood counts with differential (monthly ± 10 days)

Peripheral blood smear (every 6 months ± 30 days)

ALT, AST, Total Bilirubin or Direct Bilirubin) (monthly ± 10 days)


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
Hepatic panel (Alkaline phosphatase, ALT, AST, Total Bilirubin and Direct 
Bilirubin) (every 6 months ± 30 days)

Reticulocyte count (monthly ± 10 days)

Hemoglobin F quantification by hemoglobin electrophoresis (every 6 
months ± 30 days)

Erythrocyte adenosine deaminase (every 12 months ± 30 days)

Copper and zinc levels (every 12 months ± 30 days)

Ferritin (monthly ± 10 days); full iron panel (ferritin, transferrin, % 
saturation, and total serum iron) preferred but not required

Pregnancy test (blood or urine HCG in women of child bearing potential) 
(every 6 months ± 30 days)

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. Iron stains will be 
performed at the PI’s discretion as indicated by clinical status or laboratory 
testing. (every 6 months ± 30 days)

Bone marrow chromosomal analysis via standard cytogenetic techniques 
(every 6 months ± 30 days)

HRQL survey administration (every 6 months ± 30 days)

Iron panel (ferritin, transferrin, % saturation, total serum iron; every 6 
months ± 30 days)

MRI T2* imaging to assess liver iron concentration (every 6 months ± 30 days 
during the first year of extended phase, and then if deemed necessary by the 
PI every 12 months ±30 days thereafter)

24-hour urine collection to determine the total iron content at PI’s discretion 
if indicated for iron metabolism and excretion studies (every 6 months ± 30 
days)

Document Drug Accountability

Review of interval history and events, and physical examination (every 6 
months ± 30 days)

Review of transfusion records (if available, every 6 months ± 30 days)

Pediatric consult (every 6 months ± 30 days) at PI’s discretion

Research blood as detailed in §7 (every 6 months ± 30 days)
6.5.2.
Subjects who have EPAG discontinued after tapering for a robust response during 
the extended access phase (see Table 3) will be followed in the following manner 
(up to 3 years after the 6-month visit):


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
Complete blood counts with differential (monthly ± 10 days for 6 months off 
eltrombopag, then every 3 months ± 30 days until they reach off study 
criteria as per §8.6 or the study is closed)

Ferritin (monthly ± 10 days for 6 months off eltrombopag, then every 3 
months ± 30 days until they reach off study criteria as per §8.6 or the study 
is closed)

Iron panel (ferritin, transferrin, % saturation, total serum iron; every 12 
months ± 60 days)

Hemoglobin F quantification by hemoglobin electrophoresis (every 12 
months ± 60 days)

MRI T2* imaging to assess liver iron concentration (every 12 months ± 60 
days if the PI deems necessary, if drug is discontinued during first year of 
extended phase, also obtain imaging at the 6-month visit as above in §6.5.1)

Erythrocyte adenosine deaminase (every 12 months ± 60 days)

Peripheral blood smear (every 12 months ± 60 days for three years)

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. (every 12 months 
± 60 days for three years)

Bone marrow chromosomal analysis via standard cytogenetic techniques 
(every 12 months ± 60 days for three years)

HRQL survey administration (every 12 months ± 60 days for three years)

24-hour urine collection to determine the total iron content at PI’s discretion 
if indicated for iron metabolism and excretion studies (every 12 months ± 60 
days)

Research blood as detailed in §7 (every 12 months ± 60 days)

Review of interval history and events, and physical examination (every 12 
months ± 60 days)

Review of transfusion records (if available) 
Patients who discontinue EPAG according to the response criteria who need to have EPAG 
reinitiated due to counts falling (see §5.3) will go back onto the evaluation schedule for patients 
on EPAG in the extended access phase.
6.6.
Off study assessment
We will offer patients a follow-up evaluation at the NIH 6 months following being taken off EPAG 
treatment either due to lack of response or for the other reasons listed in §8.6, but this visit will 


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not be required. If they do not return to the NIH, we will contact their primary hematologist for 
information on their current hematologic status 6 months following their final dose of EPAG, and 
then take them off study.
If patients do return to the NIH at 6 months (± 30 days) for the off-study assessment, the following 
may be performed, and then the patient will be taken off study:

Review of interval history and events, and physical examination

Neurodevelopmental assessment (if previously performed)

CBC with differential

Hemoglobin F quantification by hemoglobin electrophoresis

Erythrocyte adenosine deaminase

Acute care panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)

Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium)

Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin)

Other (Total Protein, CK, Uric Acid, and LDH)

Reticulocyte count

Peripheral blood smear

Bone marrow biopsy with reticulin and collagen staining and aspiration with cytogenetics

Research blood as detailed in §7

Iron panel (ferritin, transferrin, % saturation, total serum iron)

MRI T2* imaging to assess liver iron concentration, if being followed per above

24-hour urine collection to determine the total iron content at PI’s discretion if indicated 
for iron

Review of transfusion records (if available)
6.7.
MRI Imaging to Assess Iron Loading
Liver iron concentration should be assessed using MRI-based techniques. Hepatic effective T2 
(T2*) magnetic resonance imaging sequences will be used, comparing observed signal relaxation 
to expected and experimentally derived controls to determine iron concentration. Native T1 
mapping and fat-water separation sequences may also be obtained to better characterize the liver. 
Contrast is not required for these studies, and contrast allergy is therefore not considered 
exclusionary. The hepatic imaging will be targeted toward assessment of iron deposition of the 
liver and will not include a comprehensive abdominal assessment.  Therefore, any additional 
questions of liver and abdominal pathology would require a separate clinical MRI scan. Although 
the sequences chosen should focus upon the liver, note will be made, where possible, of signal 
within the heart. Additional, cardiac-specific sequences are not required unless indicated for good 
clinical care. Likewise, imaging of other organs such as the brain, are not required, unless indicated 
clinically. Although it is expected that these imaging studies will be performed utilizing one of the 


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1.5 T scanners at the NIH Clinical Center for reasons of standardization, existing protocols, and 
scheduling constraints, the choice of device is not prescribed by this protocol and will be selected 
by the responsible imaging physicians(s). However, once selected, the same scanner will be 
preferentially used for all of the studies performed on a given patient to ensure comparability, or 
should the scanner be unavailable or be changed over the course of the study, at a minimum, a 
scanner with the same field strength will be used.
Imaging should be performed during the initial enrollment evaluation, and at the 6-month primary 
endpoint evaluation. For patients continuing treatment into the extended phase, it should be 
performed at the 6-month evaluation, and then annually (i.e. 12-month evaluation, 24-month 
evaluation, etc.) thereafter while on eltrombopag if the PI deems necessary. If eltrombopag is 
discontinued less than 3 months prior to a planned MRI evaluation, that evaluation should still be 
performed as was previously planned.
Inability to perform MRI imaging due to patient age, weight, or intolerance (e.g., claustrophobia), 
will not be reported to the IRB as a deviation, but will be noted within the medical record. If 
imaging is not obtained at a given timepoint, it should nonetheless be attempted at subsequent 
timepoints according to the above schedules and level of necessity.
6.8.
Genetic analysis
Patients will undergo genetic testing as part of their initial enrollment assessments, if results are 
not available from a previous, outside assessment (see §6.1). Functional testing (e.g., ribosomal 
assembly, adenosine deaminase, etc.) will be considered for purposes of supporting a diagnosis of 
DBA but are not sufficient to substitute for genetic testing. 
Intended use: The purpose of this analysis will be to identify, if possible, a disease-defining 
mutation and to rule-out alternative diagnoses; however, it is understood that approximately half 
of all patients so screened will not have an identifiable mutation (see §2.1). The presence of a 
disease-defining mutation is not required for study inclusion, nor is its absence considered 
exclusionary (see §4.1.1). This testing will also be important to rule-out the presence of MDS-
defining mutations that would be considered exclusionary (§4.2.14). This testing will take one of 
two forms:
Patients with a familial history of a known mutation: For patients where a specific 
mutation known to cause DBA has been identified in a first-degree, biological relative (i.e. 
parent, sibling, or child), the appropriate gene-specific testing (e.g., direct sequencing, 
fluorescence-in-situ hybridization, etc.) will be performed by a CLIA-certified clinical 
laboratory.


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Patients without a familial history: For patients without a familial history of DBA, or for 
which a specific, disease-causing mutation has not previously been identified, germline 
somatic mutation analysis will be performed using the NeoGenomics “Inherited bone 
marrow failure panel”. If this specific test cannot be performed, a comparable CLIA-
certified test encompassing known DBA genes is acceptable (e.g., University of Chicago 
“Hereditary Myeloid Malignancy and Inherited Bone Marrow Failure Panel”, Cincinnati 
Children’s Hospital “Bone Marrow Failure Syndromes Panel by next-generation 
sequencing”, etc.). Unbiased whole-genome or whole-exome sequencing from outside, 
CLIA-certified sources provided by the patient or referring institution may be accepted at 
the PI’s discretion.
Privacy and Confidentiality: The results of all genetic testing will be kept confidential. DBA-
specific results (i.e. identification of a disease-causing mutation) will be linked to the anonymized, 
study-specific identifier assigned to patient at the time of enrollment to allow subgrouping of 
patient data the data analysis phase and for subgrouping of any banked biospecimens. This data 
will be stored on secure, NIH-maintained servers, accessible only to study personnel, and only for 
purposes of research. After review, the results of all genetic testing, including additional, clinically 
actionable variants will be scanned into the medical record (CRIS).
Clinically Actionable Results: Subjects will be contacted if a clinically actionable gene variant is 
discovered. Clinically actionable findings for the purpose of this study are defined as disorders 
appearing in the American College of Medical Genetics and Genomics recommendations for the 
return of incidental findings that is current at the time of primary analysis. Subjects will be 
contacted at this time and will be offered the opportunity to come to NIH (at our expense) to have 
genetic education and counseling to explain this result. If the subject does not want to come to NIH, 
a referral to a local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
7. Laboratory Research Studies
Intended use:  Blood and bone marrow will be collected during the initial phase of this study at 
the baseline and 6-month landmark timepoints, and during the extended phase of this study every 
6 months (for patients continuing on eltrombopag) or every 12 months (for patients for whom 
eltrombopag was discontinued during the extended phase). The volume to be collected shall be 60 
mL of blood, or the lesser of either 3 mL/kg or 60 mL for pediatric subjects (less than 18 years of 
age), and 10 mL of aspirated bone marrow. These samples will be for use in the correlative 
laboratory research studies listed below.


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Baseline samples may be obtained under 04-H-0012. Additionally, in selected patients we will 
collect urine for 24 hours at each of the landmark visits. These studies are not used in assessing 
the primary endpoint but are undertaken as descriptive or exploratory ancillary studies. Except 
for the urine studies all test will be performed on each subject’s material.

Extended peripheral blood and bone marrow flow cytometric phenotyping for cell surface 
or intracellular proteins (e.g. six color flow cytometry to measure primitive HSCs) and 
assessment of reactive oxygen species

Hematopoietic progenitor colony, long term-culture-initiating cell, and in vitro erythrocyte 
differentiation assays for primitive cell content and function

Studies to investigate pathways that can improve erythroid differentiation in DBA

Studies to examine ribosome function and biology

Evaluation of clonal dynamics (single/bulk cell whole exome/genome sequencing)

mRNA expression studies (RNA seq) on blood or bone marrow cells

Whole genome/exome/epigenome sequencing or targeted sequencing may be performed 
in this study to assess the presence of somatic mutations in genes known to be recurrently 
mutated in MDS/AML or novel recurrently mutated genes. The data obtained will be handled 
confidentially. The digital data will be password protected and available to only the relevant 
PI and co-investigators. The specimens will be used only to study the genetics of the rare 
disease. DNA will not be used for unrelated investigations unless permission is first granted 
by the NHLBI IRB as well as the subject. We do not intend to report mutations in genes 
associated with disease risk that are incidental to our research aims, commonly referred to 
as "incidental findings."

Serum cytokine, chemokines and soluble receptor levels including but not limited to IFN-, 
TNF- and TPO levels.

Pharmacokinetic studies of EPAG kinetics (selected patients)

Should there be any remaining sample, it will be stored with the subject’s permission for 
other exploratory laboratory research studies reviewed and approved by the IRB and listed 
in APPENDIX A: Schedule of Activities.
Storage: Research samples will be stored coded in the secure laboratory of Cynthia Dunbar, M.D.
Tracking: 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. Specimens will be entered in the NHLBI Biospecimen Inventory 
System (BSI). Samples will not be sent outside the NIH without an executed MTA.
End of study procedures: Samples from consenting subjects will be stored until they are no 
longer of scientific value or if a subject withdraws consent for their continued use, at which time 
they will be destroyed.


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Loss or destruction of samples: Should we become aware that a major breech in our plan for 
tracking and storage of samples has occurred, the IRB will be notified.
8. Biostatistical Considerations
8.1.
Objectives
The primary objective is to evaluate safety and efficacy of 6 months of therapy with eltrombopag 
in subjects with Diamond-Blackfan anemia.
The secondary objectives include assessments of the impact of eltrombopag upon rates of relapse 
and survival, clonal evolution, toxicities of extended therapy, the impact of treatment upon health-
related quality of life and neurodevelopment in pediatric patients, and the impact of eltrombopag 
upon stem cell and erythroid cell dynamics and niche interactions including iron homeostasis.
8.2.
Endpoints
8.2.1.
Primary endpoint
Primary efficacy endpoint will be the proportion of drug responders at 6 months. Best 
response (robust or not) will be noted, regardless of when it is achieved; however, for 
protocol purposes, primary response will be assessed according to patient status at the 
time of the 6-month primary endpoint assessment. Time-to-response will also be measured 
according to the time from eltrombopag initiation to the first time the patient met criteria 
for response. 
Response to treatment will be defined by one or more of the following:

Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL 
will be defined as an increase in hemoglobin by >1.5 G/dL from enrollment baseline, 
and/or

a reduction in the units of PRBC transfusions by at least 50% during the eight 
consecutive weeks prior to response assessment - compared with the pretreatment 
transfusion number in the previous 8 weeks.
Robust response to treatment will be defined both:

Stable hemoglobin (two consecutive measurements at least 2 weeks apart) greater 
than 10 g/dL, and

Transfusion independence for the previous 8 weeks


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For sub-analyses, transient response to treatment (robust or otherwise) is defined as any 
response meeting the respective criteria above within the first 6 months that is 
subsequently lost and not regained prior to the 6-month primary endpoint assessment. 
While note will be made of such patients, for the purposes of primary response analysis, 
these patients will be considered non-responders along with patients who fail to meet the 
above response criteria.
Primary safety endpoint will be the toxicity profile assessed at 6 months using CTCAE 
criteria.
Transfusion Units: In pediatric patients, the administration of red blood cell transfusions is 
typically weight based, typically 10-15 mL/kg, reaching a maximum of one bag of packed 
erythrocytes (300-350 mL). For protocol purposes, a “transfusion unit” for pediatric 
patients is 15 mL/kg of packed erythrocytes. For adults and pediatric patients weighing 
approximately 20 kg or greater, “units” will be measured in bags. Where ambiguity exists, 
the clinical record shall be reviewed to determine the intent of the ordering physician as to 
whether dosing was per-bag or on a weight basis. It will be the responsibility of the PI to 
adjudicate any remaining ambiguity. Transfusions administered for non-disease 
indications (e.g., trauma, acute blood loss, perioperative hemostasis, etc.) will be noted, but 
not included in statistical and response considerations.
8.2.2.
Secondary endpoints
Secondary endpoints will include:

Hematological responses at 3 months (as defined above)

Time to response

Best response, regardless of response status at primary endpoint

Impact on platelet count and neutrophil count

Relapse during the extension phase

Clonal evolution, according to cytogenetic, mutational or flow cytometric markers

Toxicities with extended duration of therapy

The impact of treatment and treatment response on quality of life.

Evaluation of neurodevelopmental changes at baseline and 6-month evaluations.

Iron loading as measured by ferritin trends at each evaluation, and by iron staining 
of bone marrow biopsies at baseline and 6-month evaluations (and during extension 
at the PI’s discretion)

Evaluation of reactive oxygen species HSPCs (ROS flow cytometry assay at baseline 
and 6 months), and at interval evaluations during extended access at the PI’s 
discretion


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
Evaluation of global transcriptome in HSPCs (single cell RNA seq at baseline and 6 
months)

The impact of eltrombopag on reconstitution of the stem cell compartment 
(multicolor flow cytometry of bone marrow cells) and erythroid compartment 
(multicolor flow cytometry and CFU-E/BFU-E assays) at baseline and 6-month 
evaluations, and at interval evaluations during extended access at the PI’s discretion
8.3.
Sample size
Because the efficacy of eltrombopag in this patient population is unknown, we would like to reject 
the treatment as quickly as possible with a small number of patients if the treatment is not 
effective. We will use the Two-Stage Minimax Design outlined in Table 1 of Simon (89) with a 
response probability of 10% or less to terminate the treatment and the hypothesized actual 
response probability of 30% or more. The sample size is determined by testing the null hypothesis 
H0: p ≤ 10% versus the alternative H1: p ≥ 30% at a significance level of 0.05 and a power of 0.8.  
At the first stage, we will accrue 15 subjects, and the null hypothesis will be accepted if no more 
than 1 subject responds to the treatment at 6 months. If 2 or more subjects respond to the 
treatment at 6 months at the first stage, then we will accrue an additional 10 subjects, bringing the 
total number of subjects to n = 25. The null hypothesis of p ≤ 10% will be accepted if the total 
number of responders at 6 months is 5 or less. These efficacy thresholds were selected as being 
clinically relevant for the avoidance of alternative therapies such as hematopoietic stem cell 
transplant. Given an observed screening fail rate of 16.7%, we will recruit 30 patients (18 in the 
first phase, 12 in the second phase) to ensure that the target of 25 eligible patients is reached.
With an incidence of approximately 1 in 100,000-200,000 live births (18), and an expectation of 
approximately 25-35 new diagnoses a year in the USA, of which 15-20 will likely prove refractory 
to treatment, and in conjunction with recruitment through patient networks and ongoing natural 
history studies at the NIH (see §10.1), accrual is projected to take 2.5-3 years.
8.4.
Statistical methods
The change of quality of life measure from baseline will be examined by the t-test or the 
nonparametric rank-based test. The planned analyses will include descriptive statistics on the 
proportions of responses (i.e. % subjects with treatment response) and the time to response. The 
response probabilities will be estimated using the sample proportions and their inferences 
including confidence intervals and hypothesis testing will be evaluated using Binomial 
distributions.
The time to responses and the progression-free survival will be analyzed using appropriate tools 
in survival analysis, such as cumulative incidence estimate, Kaplan-Meier curves, and Cox 
regression with age, gender and ethnicity as covariates, which take consideration of both death 


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without the event of interest as a competing risk and random censoring due to loss of follow-up. 
The Kaplan-Meier estimates and Cox regression will be used to evaluate the treatment effects on 
the overall survival. Graphical tools will be used to display the appropriate estimates (i.e. 
estimated proportions, the cumulative incidence curves, Kaplan-Meier curves) and their 
corresponding 95% confidence intervals. Exploratory subgroup analysis will be used to compare 
the possible different response rates among male, female and different age categories.
8.5.
Stopping rules
The study will be monitored to ensure that the occurrence of a specified set of treatment related 
serious adverse events (TRSAEs) that occur during the treatment period does not substantially 
exceed an anticipated rate. The following specified TRSAEs determined to be probably or 
definitely related to EPAG will be considered for early stopping of the study:
1. Death considered to be probably or definitely related to eltrombopag
2. Any Grade IV toxicity excluding readily reversible metabolic or laboratory abnormalities
3. Grade IV thrombosis/embolism
We anticipate the rate of these specified TRSAEs within the 24-week study period to be 20% or 
less. Following Geller et al. (90), our stopping rule is determined by a Bayesian approach. The 
stopping boundary for an experiment is reached if the Bayesian posterior probability that the true 
probability of developing one or more of the specified TRSAE’s exceeds this benchmark rate of 
20% is at least 90%. We take our prior distribution to be a beta distribution with parameters (α, 
β) = (1, 4). The parameters are chosen so that the mean α / (α + β) = 0.2 as the expected proportion 
of specified TRSAE’s and the sum α + β = 5 as the “worth” we place on our prior clinical opinion. 
This indicates that the relative weight we place on our prior opinion is 5/25=20% of the weight 
we will place on the results of the new study.  Hence when we make decisions about stopping the 
study, the data from the study will dominate over the prior opinion.   All participants will be 
included in monitoring and evaluation for safety. Table 5 summarizes the threshold numbers for 
stopping the study.
Table 5: Threshold numbers for stopping the study
Number of subjects in the 
experiment
Stop if the number of subjects who have 
developed any of the specified TRSAE’s 
reaches:
≤ 5
3
≤ 9
4
≤ 12
5
≤ 16
6
≤ 20
7
≤ 24
8


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Number of subjects in the 
experiment
Stop if the number of subjects who have 
developed any of the specified TRSAE’s 
reaches:
25
9
We investigated the performance of the above stopping rule by a simulation study. In each 
simulation run, we generated a study with 25 independent Bernoulli trials, each had a probability 
p for having TRSAE and q=1-p for not having 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. Table 6 
summarizes the proportion of stopped studies under a number of scenarios for p:
Table 6: Predicted rates of stopping under various scenarios
Probability of TRSAE = p
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
Proportion of stopped 
studies
1.8%
7%
18.2%
35.7%
55.5%
73.2%
86.4%
94.1%
Average number of 
subjects
24.7
23.9
22.4
20.1
17.3
14.5
11.8
9.7
Average number TRSAEs
2.5
3.6
4.5
5
5.2
5.1
4.7
4.3
These simulation results suggest that our stopping rule has a low probability stopping a study 
when the proportion of TRSAE within the 24-week is below 20%, and the probability of stopping 
a study is high when the true proportion of TRSAE within the 24-week exceeds 20%.  Therefore, 
we believe that our Bayesian stopping rule for TRSAE has satisfactory statistical properties.
8.6.
Off study criteria
Per subject choice: Subjects may withdraw from study at their request. The risks of withdrawing 
will be discussed, as will alternative treatment options.  Those subjects who choose to withdraw 
while taking eltrombopag will be strongly encouraged to continue to have labs monitored until 
he/she initiates alternative therapy.
Per principal investigator decision: Should any of the following events occur during the study 
period, or in the extension treatment arm in responders, EPAG will be discontinued. The subject 
will be followed until resolution of the event. For study purposes labs relevant to the adverse event 
will be monitored for 30 days after discontinuation of EPAG. We will offer patients a follow-up 
evaluation at the NIH 6 months following being taken off EPAG treatment either due to lack of 
response or because they met other criteria for coming off study, but this visit will not be required. 
If they do not return to the NIH, we will contact their primary hematologist for information on 
their current hematologic status 6 months following their final dose of eltrombopag, and then take 


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them off study. If a patient initiates an alternative disease directed therapy at any time, the 
subject’s participation on this study will be considered complete and the subject will go off study.

Intolerance of EPAG not resolved by dose reduction

Life threatening acute hypersensitivity reaction

Thrombosis/embolism (DVT, PE, stroke or TIA, myocardial infarction) other than central 
line thrombosis

Persistent hepatotoxicity as defined in §10.3.1

New or worsening morphological abnormalities or cytopenia(s) indicative for 
transformation to MDS or AML

No treatment response by week 24 (+/- 7 days)

Any Grade IV toxicity considered related to the study medication excluding readily 
reversible metabolic or laboratory abnormalities or hematologic toxicities (see §9.2.1, 
10.3.1)

Significant progression of disease such as development of a solid tumor while on EPAG, or 
a concomitant condition that would make the subject ineligible for further protocol 
participation

Pregnancy or unwillingness to use acceptable forms of contraception

Initiation of non-protocol therapy for Diamond-Blackfan anemia

Subject non-compliance

Lost to follow-up
o
Multiple, good-faith efforts will be made according to good standards of clinical 
research to re-establish contact with any subjects prior to declaring them lost to 
follow-up and removed from study

Study completion
Completion of protocol participation: Three years after a responding patient agrees to continue 
the drug on the extension phase, protocol participation will be deemed complete. During the initial 
consenting process, the patient will be informed that eltrombopag cannot be provided after study 
completion. For responding patients wishing to continue eltrombopag, we will assist the referring 
physician with helping the patient obtain eltromobopag, including via the Novartis Patient 
Assistance Program.  Once off study, subjects will be referred back to the referring physician or 
consented to the Hematology Branch evaluation and treatment protocol (94-H-0010) or evaluated 
for eligibility for another Branch protocol, depending on the wishes of the subject and availability 
of appropriate additional clinical trials at the NIH.
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9. Data and Safety Monitoring
9.1.
Safety Monitoring
Principal Investigator: Accrual, efficacy and safety data will be monitored by the Principal 
Investigator, David J Young, M.D., Ph.D.
NIH Intramural IRB: Prior to implementation of this study, the protocol and the proposed patient 
consent and assent forms will be reviewed and approved by the properly constituted Institutional 
Review Board (IRB) operating according to Title 45 CFR 46.  This committee will also approve all 
amendments to the protocol or informed consent, and conduct continuing annual review so long 
as the protocol is open to accrual or follow up of subjects.
NHLBI Hematology DSMB: The NHLBI Hematology Data Safety and Monitoring Board (DSMB) 
will review the protocol at 6- to 12-month intervals, and the interval will be determined by DSMB. 
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.
Monitoring: As per ICH-GCP 5.18 and 21 CFR 312.50, clinical protocols are required to be 
adequately monitored by the study sponsor.  The monitoring of this study will be conducted by an 
independent contract organization 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);
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) 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.


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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 NIH IRB, the site monitors, and 
the NHLBI staff for confirmation of the study data.
FDA and IND 104877: An annual progress report, protocol amendments, and any information 
amendments (e.g., change in the status of the protocol) will be forwarded to FDA Project Manager 
(designee):
Regulatory Health Project Manager, Food & Drug Administration Document Room
Center for Drug Evaluation and Research
Division of Hematology Products
5901-B Ammendale Road
Beltsville, MD 20705-1266
phone: (301) 796-0683
Novartis: Progress reports, any amendments to the protocol, and any change in the status of the 
protocol will be forwarded to
Dram Laine, Sr. Clinical Research Scientist
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936-1080
phone: (862) 778-7281
dram.laine@novartis.com
9.2.
Event Characterization and Reporting
Events include adverse events (AE), serious adverse events (SAE), protocol deviations (PD), 
unanticipated problems (UP), and non-compliance.
The principal investigator will review all events (AEs, SAEs, PDs, UPs and non-compliance) to 
determine the seriousness, expectedness, and reportability of the event. As required and/or 
needed, the principal investigator will review the events with the Sponsor to make the final 
determination of seriousness and reportability.
9.2.1.
Definitions
Please refer to Policy 801 “Reportable Research Events” for current definitions.
9.2.2.
Adverse events Management
AEs will be graded by severity utilizing CTCAE version 5.0 (summarized in Table 7) and 
attributed (unrelated, unlikely, possibly, probably or definitely) to study medication 
and/or disease (Table 8).  The current CTCAE grading criteria can be downloaded from the 
CTEP homepage at:


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https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Table 7: Grading of adverse events
Grade
Category
Description
1
Mild
Mild; asymptomatic; clinical or diagnostic observations only; 
intervention not indicated
2
Moderate
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL1
3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2
4
Life 
threatening
Life-threatening consequences; urgent intervention indicated
5
Death
Death related to AE
1Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
2Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Table 8: Attribution of adverse events
Relationship
Attribution
Description
Unrelated
The AE is clearly NOT related to the intervention
Unrelated to investigational
agent/intervention1
Unlikely
The AE is doubtfully related to the intervention
Possibly
The AE may be related to the intervention
Probably
The AE is likely related to the intervention
Related to investigational
agent/intervention1
Definitely
The AE is clearly related to the intervention
1NOTE: AEs listed as ‘possibly, probably, or definitely’ related to the investigational agent/intervention are 
considered to have a suspected ‘reasonable causal relationship’ to the investigational agent/intervention 
(ICH E2A).
In view of the underlying disease (Diamond-Blackfan anemia), all patients will enter the 
study with abnormally low blood counts that would meet criteria for grade 2 and more 
commonly higher toxicity. Also, platelet and red blood cell counts will be impacted by 
frequent transfusions. Therefore, AEs regarding low hematologic lab values, including 
thrombocytopenia or platelet-transfusion dependence, anemia or red cell transfusion 
dependence, neutropenia, lymphopenia, or leukopenia are not evaluable and will not be 
recorded.
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 grade 3 or 4 laboratory toxicity or are 
characterized by any of the following:


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
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.
Adverse Events that meet the criteria of CTCAE v 5.0 grade 2 and above plus laboratory 
abnormalities that meet the definition of an AE will be captured at each study visit on the 
appropriate case report form (CRF) regardless of relationship. AEs and SAEs whether 
volunteered by the patient, discovered by study personnel during questioning, or detected 
through physical examination, clinically significant laboratory test, or other means will be 
recorded. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study drug and study procedure (assessed only by 
those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. These AEs will be followed to adequate resolution.
Abnormal non-hematologic laboratory values recorded in the database will be recorded at 
the highest grade and resolved in the database when the value is a grade 2 or lower. 
However, with the exception of ALT, AST and direct bilirubin any laboratory abnormalities 
higher than grade 2 will automatically result in discontinuation of the study drug.
Hypertension CTCAE v5 Grade 1 is not an applicable category for this study and therefore 
only hypertension greater than grade 2, that require medical intervention, will be 
documented.
Unscheduled laboratory results or patient reports that have been sent in addition to the 
protocol required ones will be reviewed for AEs and will be recorded on secure network 
drives or in approved alternative sites that comply with NIH information security 
standards and not in the research database.
Thirty days after the last dose of study drug, adverse event collecting and reporting will be 
limited to serious adverse events considered possibly, probably, or definitely related to 
study drug.
9.2.3.
Serious Adverse Events Management
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 


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(doubtfully related to the research) and unrelated (clearly not related to the research) 
(Table 8).
Treatment related SAEs (TRSAEs) are those attributed as definitely, probably, or possibly 
related (Table 8) that will be monitored and considered for early stopping of the study 
according to statistically determined criteria.  These include death and any grade IV toxicity 
considered to be probably or definitely related to study medication.
Hospitalizations for administrative issues (to receive a transfusion) or upgrading to ICU for 
routine monitoring will not be considered as SAE.
9.2.4.
Reporting events
All events will be reported to the Principal Investigator of this study:
David J. Young, M.D., Ph.D., TSCBB, NHLBI, NIH, Clinical Center
10 Center Dr. Building 10, Room CRC 5-3150
Bethesda, MD 20892-1452
Tel:
(301) 827-7823
Fax:
(301) 827-0915
E-mail: david.young2@nih.gov
9.2.4.1.
NIH Intramural IRB and NHLBI Clinical Director (CD) Reporting
Expedited Reporting:
Events requiring expedited reporting will be submitted to the IRB per HRPP Policy 
801 “Reporting Research Events”.
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.
Reports to the CD:
The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting 
requirements and timelines.
9.2.4.2.
NHLBI DSMB Reporting
Reports of serious adverse events that are unexpected and thought to be related 
(possible, probably or definitely) to the experimental drug will also be forwarded 
no later than seven days in the case of death or life-threatening serious adverse 


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events or within fifteen days after the occurrence of all other forms of serious 
adverse events to the Data and Safety Monitoring Board (DSMB). All SAEs will be 
included in the DSMB reports for review by the DSMB at the time of scheduled 
DSMB meetings (DSMB meetings held 2 times a calendar year and DSMB 
determines the frequency of protocol review per DSMB minutes).
9.2.4.3.
Sponsor and FDA Event Reporting
IND Sponsor:
NHLBI OCD
IND Sponsor Representative:
Cynthia E. Dunbar, MD, TSCBB, NHLBI
The PI will report SAEs to the Sponsor according to the requirements of 21 CFR 
312.64(b) and as agreed upon with the sponsor. The Sponsor (or designee) will 
determine the reportability of the event to the FDA and IND safety report will be 
submitted to the FDA as required as either an IND Safety Report or Annual report.
IND Annual Report
A summary of all SAEs, non-serious AEs, and other events will be recorded and 
submitted to the Sponsor and FDA in annual progress reports (21 CFR 312.64(b)).  
Annual progress reports will be submitted within 60 days after the anniversary 
date of the IND.
IND Safety Reports to the FDA (Refer to 21 CFR 312.32)
The sponsor must notify the FDA in an IND safety report of potential serious risks, 
from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies 
for reporting.  The sponsor must also notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.
15-day reporting
The sponsor must report any suspected adverse reaction that is both serious and 
unexpected. The sponsor must report an adverse event as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the drug 
and the adverse event, such as:


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
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome);

One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to 
the drug (e.g., tendon rupture);

An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group
The sponsor must submit each IND safety report on a MedWatch form (Form 
FDA 3500A) or in a narrative form to the Project Manager.
9.3.
Reporting Serious Adverse Events to Novartis
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided informed consent and until at least 30 days after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Information 
about all SAEs is collected and recorded on a Serious Adverse Event Report Form. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), complete the SAE Report Form in English, and send the 
completed, signed form along with the Novartis provided fax cover sheet to the Novartis 
Oncology Drug Safety and Epidemiology (DS&E) department by fax (fax: 877-778-9739) or 
via email (email: clinicalsafetyop.phuseh@novartis.com) 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 


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event has resolved or continues, if and how it was treated, 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.
9.4.
Reporting of pregnancy
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be reported by the investigator to the Novartis Oncology Drug Safety and 
Epidemiology Department (DS&E) by fax (fax: 877-778-9739) or via email (email: 
clinicalsafetyop.phuseh@novartis.com). In the case of adverse pregnancy outcomes, follow up 
should include an assessment of the possible relationship to the investigational drug.  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.
Further advice on the length of post-natal follow up can be sought from the Novartis Pediatric 
Advisory Group and should be driven by the type of congenital abnormality expected.
9.5.
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 


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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.
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.
Research data will be prospectively collected by authorized Investigator personnel and entered 
into the NHLBI approved Database. The data base is, 21 CFR 11 compliant and 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. 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 NHLBI approved 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.
Data with subject personal identifiers may be sent to associate investigators and collaborators 
outside of the NIH only after 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. Cynthia Dunbar under the supervision 
of Dr. David 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:


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
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.
Tracking: 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. Samples will not be sent outside NIH without an executed MTA 
or CTA. Identifiable samples will not be sent without IRB approval.
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 NIH Institutional 
Review Board (IRB), will be able to inspect and copy confidential study-related records which 
identify participants by name. Therefore, absolute confidentiality cannot be guaranteed.
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. Future research use of identifiable data not 
defined in the research protocol may occur only after IRB review and approval. 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 to contractual 
obligations (e.g., CRADAs) or intellectual property proceedings (such as patent filings) will be 
honored.
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: NIH Public Access Policy, which ensures that the public has access to the 


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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.
This study will comply with the 2023 NIH Data Management and Sharing Policy and Policy on the 
Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and 
Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov.
9.6.
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 or OHSRP approval, as 
applicable. Biospecimens may be destroyed only when permitted by the clinical director.
Any future research use of biospecimens not defined in the protocol in which NHLBI investigators 
are engaged in research (e.g., they are undertaking research activities and hold the key that 
identifies research subjects) requires IRB review and approval. , and an executed transfer 
agreement. 
10.Human Subject Protection
10.1.
Rationale for subject selection
With an incidence of about seven cases per million live births each year in the US and with a 50-
60% expected rate of refractory disease and/or failed first-line therapy, DBA constitutes a rare 
disease (18). The study will be open to all subjects who satisfy the inclusion criteria and provide 
an informed consent to the protocol, or have a guardian authorized to provide consent on their 
behalf. No subjects will be excluded from participation based on gender, race or ethnicity.
For subjects of Asian ethnicity:  Plasma EPAG area under the curve was approximately 70% 
higher in East and South East Asian (ethnicity self-reported) subjects as compared with 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 EPAG has been studied in adult 
patients with renal impairment. Following administration of a single 50 mg dose, there was a trend 
for reduced plasma EPAG exposure in patients with renal impairment, but there was substantial 
variability and significant overlap in exposures between patients with renal impairment and 


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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 EPAG have been studied in adult 
patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ 
of EPAG was increased by 41% in subjects with mild hepatic impairment and by 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: The study may use the following strategies of recruitment including:

ClinicalTrials.gov website

Clinical Center Research Studies (“Search the Studies”) website

Diamond-Blackfan Anemia Foundation, Inc. (dbafoundation.org) website

National Heart, Lung and Blood Institute (NHLBI) patient recruitment website

Twitter messages and chats with study investigators

Facebook Posts

Google Ad Words

In collaboration with the National Cancer Institute (NCI) Inherited Bone Marrow Failure 
Syndrome Study (IBMFS), a natural history Cohort Study

Use of Clinical Center Office of Patient Recruitment services including creation and 
distribution of study flyers and information through pre-existing recruitment avenues such 
as the NIH recruitment listserv.
The DIR Patient Recruitment Office (PRO) will work with study investigators to ensure accrual 
goals are being met.  Biannual reviews will be performed by investigators and the PRO.  If 
recruitment goals are lagging, an enhanced plan of recruitment will be triggered, which may 
include a communication blitz to known and newly contacted hematologists and oncologists 
throughout the country; additional Twitter feeds and chats, Facebook posts and recirculation of 
updated and/or new patient recruitment flyers.  All recruitment materials and tools will use IRB-
approved language and information to include standard recruitment contacts.
Recruitment language to be used:
Do you know someone with Diamond-Blackfan anemia (DBA)?
Researchers at the National Institutes of Health (NIH) in Bethesda, Maryland are 
conducting an investigational treatment study with eltrombopag to help patients with 
Diamond-Blackfan anemia (DBA). Eligible volunteers must be diagnosed with DBA, 
especially DBA that has not responded to or recurred despite standard therapies. DBA 


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is an inherited disease that can lead to anemia and ultimately bone marrow failure, 
with increased risks of cancer. Eltrombopag is a drug that can help patients with 
aplastic anemia, an acquired bone marrow failure syndrome.  Whether it can also help 
patients with different, inherited bone marrow failures is a point of ongoing research 
at the NIH. This study will attempt to determine whether eltrombopag is safe and 
effective for patients with DBA. 
Though considered primarily a blood disease, DBA may affect all systems of the body, 
especially as the treatments involved (chronic transfusions and/or steroids) have 
wide-ranging effects. Eltrombopag has been shown to help reduce the iron that can 
build up in DBA patients, and consequently may help reduce some of these side effects. 
In addition to investigating whether eltrombopag can improve blood cell counts in 
DBA patients, this study will help answer this question. Travel, food and lodging may 
be provided consistent with guidelines of the National Heart, Lung and Blood Institute 
policies. 
Study Design:

1-2 visits to the NIH Clinical Center in Bethesda, Maryland before starting drug 
and then every 6 months while on drug

Patients will take eltrombopag over a 6-month period

Patients who exhibit improvements after 6 months of taking eltrombopag may 
be eligible to continue taking eltrombopag for up to 3 additional years
Who Can Participate:

Patients 2 years or older diagnosed with Diamond-Blackfan anemia (DBA)

Patients diagnosed with DBA who have not responded to therapy, have 
relapsed, and/or are unable to tolerate current therapy   

Patients willing to take eltrombopag for a minimum of 6 months

Patients willing to have their blood drawn every two weeks by your home 
physician
The NIH Clinical Center, America’s Research Hospital, is located in Bethesda, 
Maryland, on the Metro red line (Medical Center stop).


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For more information: 
NIH Clinical Center Office of Patient Recruitment 
866-444-1132
TTY users call via MD Relay 7-1-1
Se habla español
Email: PRPL@cc.nih.gov
NIH Study: 20-H-0021
For shorter recruitment materials such as Twitter or Facebook one of the following shall be used:
Option 1 (Post):
Do you or someone you know have Diamond-Blackfan anemia (DBA)? Researchers at 
the National Institutes of Health (NIH) in Bethesda, Maryland are conducting an 
investigational treatment study with eltrombopag to help patients with DBA. 
Treatment and research procedures are provided at no cost. Contact us at 1-800-411-
1222, PRPL@cc.nih.gov. Refer to study # 20-H-0021
Option 2 (Post):
NHLBI researchers are looking for patients who have been diagnosed with Diamond-
Blackfan anemia (DBA). Eligible volunteers must be diagnosed with DBA, especially 
DBA that has not responded to or recurred despite standard therapies. To learn more 
about this study, call the Office of Patient Recruitment at 1-800-411-1222 (refer to 
study # 20-H-0021)
Option 3 (Post):
Though considered primarily a blood disease, Diamond-Blackfan anemia (DBA) may 
affect all systems of the body, especially as the treatments involved (chronic 
transfusions and/or steroids) have wide-ranging effects. Researchers at the National 
Heart, Lung, and Blood Institute are conducting an investigational treatment study 
with eltrombopag to help patients with DBA. Eltrombopag has been shown to help 
reduce the iron that can build up in DBA patients, and consequently may help reduce 
some of these side effects. To learn more about this study, call the Office of Patient 
Recruitment at 1-800-411-1222 (refer to study # 20H0021) [URL shorten version] 
Option 4 (Tweet):
Researchers at the @NHLBI need patients who have been diagnosed with Diamond-
Blackfan anemia (DBA). NIH Clinical Center Office of Patient Recruitment at 1-800-


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411-1222. Refer to study # 20-H-0021
Option 5 (Tweet):
Researchers from @TheBethesdaLabs and @NIHClinicalCntr are seeking volunteers 
diagnosed with Diamond-Blackfan anemia, especially DBA that has not responded to 
or recurred despite standard therapies. #ResearchMatters
Option 6 (Tweet):
Do you know someone with #DiamondBlackfanAnemia (DBA)? @TheBethesdaLabs is 
seeking volunteers for a study with eltrombopag to help #patients with #DBA. 
#ResearchMatters
Option 7 (Tweet):
#HCPs: A new #clinicaltrial from @TheBethesdaLabs will determine whether 
#eltrombopag 
is 
a 
safe 
and 
effective 
treatment 
for 
patients 
with 
#DiamondBlackfanAnemia. #DBA #ResearchMatters 
Option 8 (Tweet):
#Patients diagnosed with #DiamondBlackfanAnemia may be eligible for a new 
#clinicaltrial at the @NIHClinicalCntr. Learn more: #DBA #ResearchMatters
Option 9 (Tweet):
A new #NHLBI study may provide an alternative treatment option for #patients with 
#DBA. Learn more: #ResearchMatters @NIHClinicalCntr
Reimbursement for protocol participation, travel, food, and lodging will be consistent with 
NHLBI DIR Travel and Lodging Compensation of Clinical Research Subjects policy or institutional 
guidelines.
Payment for participation:  $0 – Subjects will not be compensated for their participation in this 
study.
Competition between Branch protocols: There are no competing Branch protocols for this 
patient population.


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10.2.
Participation of Pediatric patients
As outlined in §2.2. the anemia from red cell aplasia that is the hallmark of Diamond-Blackfan 
anemia usually manifests in the first few years of life. We are currently treating pediatric patients 
with EPAG on 4 different protocols: in the combination with immunosuppression (12-H-0150), 
headed by Dr. Neal Young, protocols 11-H-0134 for patients with moderate aplastic anemia and 
13-H-0133 for patients with refractory aplastic anemia, led by Dr. David Young and Dr. Cynthia 
Dunbar, and protocol 17-H-0121 for patients with Fanconi anemia, headed by Dr. Andre 
Larochelle. Based on this experience we have now established a dosing schedule that is associated 
with very limited toxicities. However higher weight-adjusted drug clearance is possible, 
particularly in younger children. Pharmacokinetic studies (PK) in pediatric patients with 
Diamond-Blackfan anemia treated with EPAG have not been performed, although similar studies 
in patients with Fanconi anemia are ongoing (protocol 17-H-0121). Therefore, PK studies will be 
performed. If PK studies indicate significant faster drug clearance potentially affecting its efficacy, 
we will amend the protocol and adjust the pediatric dosing accordingly. Given the early 
presentation of the disease, and the importance of early intervention, we propose enrolling 
patients 2 years of age or older. As EPAG is a potent iron chelator, and given the role of iron in 
neurodevelopment, we will perform baseline and landmark neurodevelopmental testing on 
pediatric patients where possible.
10.3.
Risks and Discomforts
10.3.1.
Related to Promacta® (Eltrombopag)
Potential Serious Adverse Effects:
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.
Warnings and Precautions with eltrombopag:
Hepatic Decompensation in Patients with Chronic Hepatitis C
In patients with chronic hepatitis C, PROMACTA in combination with interferon and 


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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-1A1 (UGT1A1) and organic anion-
transporting polypeptide-1B1 (OATP1B1), 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 
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 


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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.
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.


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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 (see Table 9).
Table 9: Adverse reactions (≥10%) from one open-label trial in adults with severe aplastic 
anemia
Adverse Reaction
Eltrombopag
(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.
USE IN SPECIFIC POPULATIONS
Pregnancy


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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.
EPAG 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 EPAG 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). EPAG 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 


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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.
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 
PROMACTA 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.
Severe cutaneous reaction
There is a risk that subject may develop a severe cutaneous reaction that may require 
hospitalization and discontinuation of eltrombopag.
The safety of eltrombopag has also been studied in healthy volunteers who received the 
drug for 5 days at doses as high as 200mg daily with safety profiles similar to placebo (91).
Investigator Brochure, Version 13, dated 4/13/2016 - “Adverse Events considered to 
be Expected for Reporting Purposes”
Below are lists of “Adverse Events considered to be Expected for Reporting Purposes” for 
each chronic ITP and SAA. This list is based upon evaluation of the available clinical safety 
information, including data from all global clinical trials (phase I-III) and the Novartis safety 
database, Argus (cut-off date of 29 February 2016).
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%)


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Table 10: Adverse events considered to be expected for reporting purposes in chronic ITP 
adults
Infections and infestations
Common:
Pharyngitis
Urinary tract infection
Gastrointestinal disorders
Very Common:
Nausea
Diarrhea
Common:
Dry mouth
Vomiting
Hepatobiliary disorders
Common:
Increased aspartate aminotransferase
Increased alanine aminotransferase
Blood bilirubin unconjugated increased
Uncommon:
Drug-induced liver injury
Skin and subcutaneous tissue disorders
Common:
Alopecia
Rash
Musculoskeletal and connective tissue disorders
Common:
Back pain
Musculoskeletal chest pain
Musculoskeletal pain
Myalgia
Vascular disorders
Rare: post-marketing cases of Thrombotic microangiopathy with acute renal failure reported 
spontaneously
Table 11: Additional adverse events considered to be expected for reporting purposes in 
chronic ITP pediatric patients (aged 1 to 17 years) in addition to those seen in chronic ITP 
in adults
Infections and infestations
Very common:
Nasopharyngitis, upper respiratory tract infection
Common:
Rhinitis
Gastrointestinal disorders
Common:
Abdominal pain, toothache
General disorders and administration site conditions
Common:
Pyrexia
Respiratory, thoracic and mediastinal disorders
Common:
Cough, oropharyngeal pain, rhinorrhea
Vascular disorders
Rare: post-marketing cases of Thrombotic microangiopathy with acute renal failure reported 
spontaneously
Table 12: Adverse events considered to be expected for reporting purposes in severe 
aplastic anemia
Blood and lymphatic system disorders
Very common:
Anemia


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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
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
Table 13: Adverse events considered to be expected for reporting purposes in MDS/AML
Blood and lymphatic system disorders
Very common:
Leukocytosis**, increased white blood cell counts
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
**
“Leukocytosis” and “white blood cell counts 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
Additional Eltrombopag risks
Although the risk is considerably lower than with other forms of inherited bone marrow 
failure syndromes such as Fanconi anemia or Dyskeratosis Congenita, patients with 


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Diamond-Blackfan anemia may be at risk of developing chromosomal abnormalities and 
progressing to another form of bone marrow failure syndrome called myelodysplasia. As 
noted in the scientific justification above (§2.4.1), prior evidence indicates that 
eltrombopag acts as a chelator of iron, reducing intracellular reactive oxygen species stress, 
improving hematopoiesis and reducing the intrinsic genotoxic stresses upon erythroid 
precursors and hematopoietic stem cells. Additionally, previous work has suggested that 
eltrombopag may improve DNA repair mechanisms in hematopoietic stem cells in vivo. 
Combined, these effects may counteract or delay any naturally occurring malignant 
transformation in Diamond-Blackfan patients. However, eltrombopag stimulates stem cells 
and potentially also pre-malignant stem cells. Therefore, it is hypothetical that eltrombopag 
accelerates malignant transformation, although this has not been borne out by prior studies 
in patients with existing pre-malignant conditions.
Nonclinical Pharmacology
Studies conducted in vitro have shown that EPAG is an effective agonist binding to TPOR, 
the thrombopoietin (TPO) receptor encoded by MPL, to stimulate thrombopoiesis. It binds 
TPOR at a position distinct from the ligand binding site, and thus does not compete with 
TPO for binding to its receptor. In vivo, eltrombopag increases platelet number in the 
chimpanzee (the only nonclinical species which is pharmacologically responsive to 
eltrombopag). These findings, coupled with supporting clinical efficacy data, suggested that 
eltrombopag is an orally active TPOR agonist that functions in a similar manner to 
endogenous TPO. Additionally, in vitro electrophysiology studies have been performed and 
in vivo safety pharmacology studies assessed the effects of eltrombopag on cardiovascular, 
respiratory and central nervous systems.
Nonclinical pharmacokinetics (distribution, metabolism and excretion in animal 
models)
Comprehensive nonclinical pharmacokinetic, distribution, metabolism and excretion 
studies were conducted in the mouse, rat and dog with EPAG. Absorption of EPAG was low 
to moderate and plasma clearance was generally low with moderate to long half-lives. 
Eltrombopag-related material was widely distributed into peripheral tissues in the mouse 
and rat but the concentrations in most tissues were lower than in the blood. Drug-related 
material did not extensively penetrate into the central nervous system or the lens of the 
eye, nor was it selectively retained in melanin containing tissues. There was no evidence of 
tissue accumulation of drug-related material in mice, including eyes, kidneys and skin. 
Eltrombopag was highly bound to plasma proteins in nonclinical species as well as in 
human plasma (>99%), with low association with blood cells. Eltrombopag was the 
predominant circulating component in all species. Minor metabolites in circulation 


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included products of oxidation or glucuronidation. Eltrombopag was primarily eliminated 
as unchanged drug in the feces with renal elimination of cleavage products contributing a 
minor route. Qualitatively, all of the major metabolites of eltrombopag observed in humans 
were observed in the nonclinical species. In vitro, eltrombopag inhibited cytochrome P450 
(CYP) enzymes CYP2C8 and CYP2C9 and several uridine diphosphate glucuronosyl 
transferase (UGT) enzymes at potentially clinically relevant concentrations. Eltrombopag 
was neither an inhibitor nor a substrate of human P-glycoprotein (PGP) and was not a 
substrate of human organic anion transporting polypeptide (OATP1B1), although it was an 
inhibitor of this transporter with the potential for such an interaction confirmed clinically.
Nonclinical toxicology
There were no clinically-relevant findings in toxicity studies examining the potential effects 
of eltrombopag on the cardiovascular, respiratory and central nervous systems. In vitro, 
eltrombopag was shown to inhibit hERG (human Ether-à-go-go Related Gene), the alpha 
subunit of a voltage-gated potassium (K+) channel tail current. In an in vitro study using 
isolated dog Purkinje fibers, eltrombopag was not associated with action potential 
prolongation, but did cause decreases in the upstroke amplitude, maximum rate of 
depolarization and action potential durations. In a definitive clinical QTc study with a 
supratherapeutic dose of eltrombopag, there was no effect on cardiac repolarization.
The toxicity profile of eltrombopag has been defined in a single dose study in dogs and 
repeat dose toxicity studies of up to 13 weeks in mice, 28 weeks in rats and 52 weeks in 
dogs. In addition, repeat dose toxicity was assessed in 2-year carcinogenicity studies in 
mice and rats.
The principal nonclinical toxicology findings associated with eltrombopag treatment 
include:
Cataracts (mice and rats)
In vitro phototoxicity (3T3 and CHO cells) was observed. In mice and rats, the development 
of cataracts was dose- and time-dependent and the rapidly developing lenses of young mice 
were shown to be more susceptible. Cataract development was not associated with drug 
accumulation in ocular tissues. No treatment-related ocular abnormalities were evident in 
dogs given the maximum tolerated dose of 30 mg/kg/day (418 μg/mL) for 52 weeks based 
on detailed ophthalmologic and histologic examinations.  There was no evidence of acute 
photo-ocular toxicity in albino or pigmented rats. An apparent delay in onset and a lower 
incidence of cataracts in albino mice housed in subdued versus ambient light was observed 
suggesting that light may contribute to cataract development in young mice. However, 
there was no evidence of ocular phototoxicity in young albino or pigmented mice given 


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eltrombopag and exposed to repeated doses of solar-simulated ultraviolet radiation (UVR). 
B6C3F1 mice (a pigmented strain) given eltrombopag with or without UVR exposure 
appeared to be more susceptible than albino mice to eltrombopag-induced 
cataractogenesis. However, given that eltrombopag has not been shown to be selectively 
retained in melanin-containing tissues, this likely represents a strain difference in 
sensitivity to cataract induction.
Renal toxicity (mice and rats).
In mice, renal proximal tubular toxicity was observed following repeated oral 
administration of eltrombopag in a 2-year carcinogenicity study at 1.4-fold clinical 
exposure in ITP patients. Renal toxicity was not observed in mice in a 13-week study at a 
greater exposure (4.5-fold clinical exposure in ITP patients, respectively) than that 
achieved at the lowest dose in the 2-year study, suggesting that the renal effects are time-
dependent. In rats, an increase in the incidence or severity of spontaneous, age-related 
chronic progressive nephropathy was observed at a similar exposure level, but not at lower 
exposures. The relationship of this finding to the renal effects observed in mice is unknown. 
No renal toxicity was observed following repeated oral administration to rats for 28 weeks 
or to dogs for 52 weeks at exposures up to 4.5- and 2.9-fold clinical exposure in ITP patients.
Hepatotoxicity (mice, rats and dogs)
In mice, rats and dogs, hepatocyte degeneration and/or necrosis, often accompanied by 
markedly increased serum liver enzymes, was observed following repeated oral 
administration of eltrombopag at exposures generally associated with morbidity and 
mortality. In rats and dogs, no treatment-related hepatic effects were observed after 28 or 
52 weeks at exposures up to 4.5- or 2.9-fold clinical exposure in ITP patients.
Genotoxicity
The toxic potential of eltrombopag was also assessed in a battery of in vitro and in vivo 
genetic toxicology studies and the weight of evidence provided by these assessments 
suggests that eltrombopag does not pose a genotoxic risk in humans.
Carcinogenicity
Eltrombopag was not carcinogenic to mice or rats following 2-year carcinogenicity studies.
Teratogenicity
Eltrombopag was not teratogenic in rats or rabbits and did not affect fertility in male rats 
or fertility, early embryonic development, embryofetal development, maternal 


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reproductive function, or development of offspring in female rats at non-maternally toxic 
doses. No effect on embryofetal development was observed in rabbits. At a maternally toxic 
dose in rats, treatment with eltrombopag was associated with embryolethality, a low 
incidence of cervical ribs (a non-teratogenic fetal variation) and reduced fetal body weight. 
In definitive juvenile toxicity studies in rats, eltrombopag was not associated with adverse 
effects. In vitro, eltrombopag was toxic in the presence of ultraviolet-A (UV-A) radiation, 
indicating a phototoxic response. However, there was no evidence of cutaneous 
phototoxicity in hairless mice or ocular phototoxicity in pigmented or albino mice or rats. 
Eltrombopag also showed evidence of photoclastogenicity in vitro that was associated with 
cytotoxic drug concentrations (15 to 29 μg/mL) and high intensity UV exposure [30 
minimal erythematous dose (MED)]. However, no evidence of photoclastogenicity was 
observed at a 2-fold higher concentration (58.4 μg/mL) and UV exposure of ~15 MED. 
Eltrombopag did not adversely affect immune function in an immunotoxicity study in rats.
Clinical Pharmacology (based on studies done in healthy subjects and subjects with 
hepatic impairment or renal impairment) 
Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours 
after oral administration. Based on urinary excretion and biotransformation products 
eliminated in feces, the oral absorption of drug-related material following administration 
of a single 75 mg solution dose was estimated to be at least 52%. In a clinical study, 
administration of a single 75 mg-dose of EPAG with a polyvalent cation-containing antacid 
(1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) 
decreased plasma EPAG AUC0-∞ and Cmax by 70%. The contribution of sodium alginate to 
this interaction is not known.  An open-label, randomized, crossover study was conducted 
to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat 
breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and 
Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also 
contributed to this decrease in exposure.
Distribution: The concentration of EPAG in blood cells is approximately 50-79% of plasma 
concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is 
highly bound to human plasma proteins (>99%). Eltrombopag is not a substrate for p-
glycoprotein (Pgp) or OATP1B1.
Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through 
pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, 
or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% 
of plasma radiocarbon AUC0-∞. Metabolites due to glucuronidation and oxidation were 
also detected. In vitro studies suggest that CYP 1A2 and 2C8 are responsible for the 


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oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the 
glucuronidation of EPAG.
Elimination: The predominant route of eltrombopag excretion is via feces (59%) and urine 
(31%). Unchanged EPAG in feces accounts for approximately 20% of the dose; unchanged 
eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is 
approximately 21 to 32 hours in healthy subjects and 26-35 hours in ITP patients.
Race: Based on both non-compartment analysis and population pharmacokinetic analysis, 
plasma eltrombopag exposure was approximately 70% higher in some Asian subjects (East 
and South East Asian) with ITP as compared to non-Asian subjects who were 
predominantly Caucasian in these trials.  In addition, the pharmacodynamic (PD) response 
to eltrombopag was qualitatively similar in the Asian subjects, but the absolute PD 
response was somewhat greater. An approximately 40% higher systemic EPAG exposure 
in healthy African- American subjects was noted in at least one clinical pharmacology study. 
The effect of African-American ethnicity on exposure and related safety and efficacy of 
eltrombopag has not been established.
Gender: Results from a population pharmacokinetic model suggest that males have a 27% 
greater apparent EPAG clearance than females, after adjustment for the body weight 
difference.
Hepatic Impairment: Plasma EPAG pharmacokinetics in subjects with mild, moderate, 
and severe hepatic impairment compared to healthy subjects was investigated following 
administration of a single 50 mg dose of EPAG. The degree of hepatic impairment was based 
on Child-Pugh score. Plasma EPAG AUC0-∞ was 41% higher in subjects with mild hepatic 
impairment, and 80% to 93% higher in subjects with moderate to severe hepatic 
impairment compared with healthy subjects.
10.3.2.
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.
10.3.3.
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.  Infections may rarely occur.
10.3.4.
Related to neurodevelopmental testing


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The only anticipated adverse consequences associated with neurodevelopmental testing 
will be the time required for the participants to complete the assessment.
10.3.5.
Related to HRQL
The only anticipated adverse consequences associated with the HRQL will be the time 
required for the participants to complete the questionnaire.
10.3.6.
Related to MRI imaging
MRI imaging may cause discomfort to patients, especially patients with claustrophobia. 
Anxiolytics will be provided to patients to relieve this discomfort. For pediatric patients 
and severely affected adults, it may be necessary to provide sedation. There is no risk of 
allergic reaction in patients with a positive history as contrast (intravenous or oral) is not 
planned for these studies. There is a risk of burns or injury if metal is present in the scanner; 
patients will be pre-screened prior to all scans.
10.3.7.
Risks related to genetic testing
Accidental disclosure of genetic information derived from research testing will be unlikely 
as all samples and research data will be coded and kept separately from the patient 
demographic information. Individually identifiable genetic data directly related to this 
study will not be released to participants. We do not intend to report mutations in genes 
associated with disease risk that are incidental to our research aims, commonly referred to 
as "incidental findings." With increasing technology, it is possible that a person may be 
identifiable from their sequence data submitted as part of a publication of this material. We 
will attempt to limit this, by again using only coded specimens.
10.4.
Risks in Relation to Benefit
10.4.1.
For adult subjects
The benefits to the patients could be improvement of cytopenias (increased blood cell 
numbers) and/or reduction or even abolition of transfusion requirements, resulting in 
improved quality of life and also decreased morbidity and mortality from transfusion-
associated viral agents, and/or a susceptibility to infections. Potentially, treatment with 
other more toxic therapies could also be avoided or postponed.
10.4.2.
For children
The inclusion of children satisfies the criteria set forth in 45 Code of Federal Regulations 
46, Subpart D: 46.405 as follows:


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(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 the assent of the children and 
permission of their parents or guardians, as set forth in 46.408.
10.4.3.
For Cognitively Impaired subjects
This research provides the prospect of direct benefit; therefore, inclusion is justified. The 
benefits to the participants could be improvement of anemia 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 these potential benefits this protocol offers. There are 
no plans to include institutionalized participants. There are no known additional risks 
specific to this group that would not apply to other groups of participants.
10.5.
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 prior to entry onto the study. Consent may be obtained with required signatures on the 


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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 will 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 will 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. 
Subjects who are cognitively impaired and who lack capacity to provide consent: The 
consent process for these subjects will follow the requirements of Policy 403.
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.
Justification for inclusion: This research provides the prospect of direct benefit; therefore, inclusion 
is justified. There are no plans to include institutionalized participants.
Procedures to obtain assent and documentation of assent or dissent: The informed consent 
discussion will include the individual unable to provide informed consent along with LAR. The 
individual unable to provide informed consent will be asked if they agree to participate in the 
research and this 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 authorized parent or guardian.  For minors that are age 7 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. Age-appropriate language will be used to describe the procedures 
and tests involved in this study, along with the risks, discomforts and benefits of participation. 
Verbal assent will be obtained as appropriate for children less than 12 years of age, exclusive. 
Children under the age of 18, but who are 12 years of age or older will be asked to sign an age-
appropriate assent form. 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. 
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. The parent 
or guardian will sign on the designated line on the informed consent attesting to the fact that the 
child had given assent. All children will be reconsented upon reaching the age of 12 years, as 
described below. For pediatric patients with cognitive disabilities, the requirement for assent, 
written and/or verbal, will be adjusted as deemed appropriate by the clinician and the child’s 
parent(s) and/or guardian(s).
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).
If the minor subject is a female of childbearing age, she will be informed about pregnancy testing 
and will be told that if her pregnancy test is positive, we will counsel her and help her tell her 
parents or we will tell her parents. If she does not agree she will be advised not to sign the assent.
Minors when they reach the age of majority:  When a pediatric subject reaches age 18, 
continued participation will require consenting of the now adult subject 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 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, we are unable to contact.
The consent process for cognitively impaired minor subjects who reach the age of majority will 
follow the requirements of Policy 403.


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Requirements for Waiver of Consent consistent with 45 CFR 46.116 (f)(3), 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. Cynthia 
Dunbar under the supervision of Dr. David 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
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.
10.6.
Conflict of Interest
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 FDA and to the NHLBI Clinical 
Director.
10.7.
Collaborative Agreements
Cooperative Research and Development Agreement (CRADA)
This protocol has an associated CRADA with Novartis.
Material Transfer Agreements (MTA)
Between NHLBI (David Young, MD, Ph.D.) and Dr. Jan Abkowitz at University of Washington. Upon 
execution of the MTA, coded peripheral blood or marrow samples from 20H0021 may be sent to 
the University of Washington. The goal of this collaboration is to identify the defect in red blood 
cell development for each patient, matching these results with disease-causing mutation (if 
known) and drug response, the final goal of which is to understand the underlying cause of 


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response or lack thereof. The NIH research team will receive research results that can be linked to 
identifiers as part of this research collaboration.
11.Pharmaceuticals
11.1.
Eltrombopag (Promacta®)
Supply: Novartis
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.
Supply: The drug Novartis is providing for this study may be either investigational or 
commercial material, based on their supply.  It is available as tablets of 12.5, 25, 50 and 
75mg. It is also available as a powder for oral suspension (PfOS) that will be available in 
12.5 mg or 25 mg strength.

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 


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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
Shipping Designee Name:  Jihyun Esther Jeon
Shipping Designee Phone No: (301) 496-4363
Shipping Designee FAX No: (301) 402-3268
Shipping Designee e-mail: 
jihyunesther.jeon@NIH.gov


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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.


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12.References
1.
Boria I, Quarello P, Avondo F, Garelli E, Aspesi A, Carando A, Campagnoli MF, Dianzani I, Ramenghi U. A new 
database for ribosomal protein genes which are mutated in Diamond-Blackfan Anemia. Hum Mutat. 
2008;29(11):E263-70. Epub 2008/09/11. doi: 10.1002/humu.20864. PubMed PMID: 18781615.
2.
Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, Handsaker RE, Abdulhay NJ, Fiorini C, 
Genovese G, Lim ET, Cheng A, Cummings BB, Chao KR, Beggs AH, Genetti CA, Sieff CA, Newburger PE, Niewiadomska 
E, Matysiak M, Vlachos A, Lipton JM, Atsidaftos E, Glader B, Narla A, Gleizes PE, O'Donohue MF, Montel-Lehry N, 
Amor DJ, McCarroll SA, O'Donnell-Luria AH, Gupta N, Gabriel SB, MacArthur DG, Lander ES, Lek M, Da Costa L, 
Nathan DG, Korostelev AA, Do R, Sankaran VG, Gazda HT. The Genetic Landscape of Diamond-Blackfan Anemia. Am J 
Hum Genet. 2018;103(6):930-47. Epub 2018/12/07. doi: 10.1016/j.ajhg.2018.10.027. PubMed PMID: 30503522; 
PMCID: PMC6288280.
3.
Gazda HT, Zhong R, Long L, Niewiadomska E, Lipton JM, Ploszynska A, Zaucha JM, Vlachos A, Atsidaftos E, 
Viskochil DH, Niemeyer CM, Meerpohl JJ, Rokicka-Milewska R, Pospisilova D, Wiktor-Jedrzejczak W, Nathan DG, 
Beggs AH, Sieff CA. RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with 
RPS19 mutations. Br J Haematol. 2004;127(1):105-13. Epub 2004/09/24. doi: 10.1111/j.1365-2141.2004.05152.x. 
PubMed PMID: 15384984.
4.
Da Costa L, Narla A, Mohandas N. An update on the pathogenesis and diagnosis of Diamond-Blackfan 
anemia. F1000Res. 2018;7. Epub 2018/09/20. doi: 10.12688/f1000research.15542.1. PubMed PMID: 30228860; 
PMCID: PMC6117846.
5.
Doty RT, Phelps SR, Shadle C, Sanchez-Bonilla M, Keel SB, Abkowitz JL. Coordinate expression of heme and 
globin is essential for effective erythropoiesis. J Clin Invest. 2015;125(12):4681-91. Epub 2015/11/10. doi: 
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Kalota A, Selak MA, Garcia-Cid LA, Carroll M. Eltrombopag modulates reactive oxygen species and decreases 
acute myeloid leukemia cell survival. PLoS One. 2015;10(4):e0126691. Epub 2015/04/29. doi: 
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B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic 
thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641-8. 
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David M, Boayue KB, Matthews DC, Lambert MP, Marcello LM, Iyengar M, Chan GW, Chagin KD, Theodore D, Bailey 
CK, Bakshi KK. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia 
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RPL4 as a novel disease gene in a condition resembling Diamond-Blackfan anemia. Haematologica. 
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molecular study of three patients with novel RPL5 and mosaic RPS19 mutations. Blood Cells Mol Dis. 2017;64:38-44. 
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PMID: 20418510.


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13.Appendices
APPENDIX A: Schedule of Activities
Table 14: Schedule of Activities (Pre-enrollment through first 6 months of treatment)
Week (± 10 days2)
Visit/Time Point
Baseline1
2
4
6
8
10
123,4
14
16
18
20
22
Month 63
Month 12 
Off-study5
Clinical Assessments
Consent
X
Medical history / Interval History
X
X
X
X
Physical examination
X
X4
X
X
Pediatric consult
X
Neurodevelopmental testing
X9
X6
X
Concurrent medication review
X7
Transfusion records review
X
X
X
X
Laboratory Evaluations
Complete blood count with differential
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
Reticulocyte count
X7
X
X
X
Peripheral blood smear
X
X
X
Hemoglobin F quantification
X
X6
X
X
Erythrocyte adenosine deaminase
X
X6
X
X
DAT (direct antiglobulin test)
X
Chromosomal Breakage Analysis
X8
Genetic testing
X8
Acute care (Na, K, Cl, CO2, Creatinine, 
Glucose, and Urea Nitrogen)
X7
X
X
X
Mineral (Phosphorus, Magnesium, 
Albumin, and Calcium)
X
X
X
X
Hepatic (Alk Phosphatase, ALT, AST, Total 
Bilirubin, and Direct Bilirubin)
X7
X
X
X


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Week (± 10 days2)
Visit/Time Point
Baseline1
2
4
6
8
10
123,4
14
16
18
20
22
Month 63
Month 12 
Off-study5
Laboratory Evaluations (continued)
Hepatic (ALT, AST, Total Bilirubin, OR 
Direct Bilirubin)
X
X
X
X
X
X
X
X
X
X
Total Protein
X
X
X
X
CK
X
X
X
X
Uric Acid
X
X
X
X
LDH
X
X
X
X
Coagulation and thrombosis screens 
(PT, PTT)
X
Viral serologies:
HepA, HepB (HBsAg, HBsAb, DNA PCR), 
HCV, HIV, HSV, EBV and CMV
X
Folate level
X
B12 level
X
Metals: copper and zinc level
X
X
X
Iron panel:
ferritin, transferrin, % saturation, total 
serum iron
X
XO
XO
XO
XO
XO
X
XO
XO
XO
XO
XO
X
X
Ferritin
X
X
X
X
X
X
X
X
X
X
24-hour urine collection to determine the 
total iron
X9
X9
X9
HLA typing (if not performed & available)
X
Pregnancy test 
(blood or urine HCG in women of child 
bearing potential)
X7
X
Immunoglobulins
X
Thyroid function panel (T3, T4, and TSH)
X


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PI: David J. Young, M.D., Ph.D.
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Week (± 10 days2)
Visit/Time Point
Baseline1
2
4
6
8
10
123,4
14
16
18
20
22
Month 63
Month 12 
Off-study5
Procedures
Bone marrow aspiration and core biopsy10
X
X
X
Bone marrow chromosomal analysis via 
standard cytogenetic techniques
X
X
X
Electrocardiogram (EKG)
X
MRI (T2* liver iron concentration)11
X
X
X
Research Testing and Assessments
Research Blood
X
X
X
PK
X
HRQL survey administration
X12
X12
Document Drug Accountability
X
1 may use screening results if obtained within 7 days of consent, unless indicated otherwise
2 all timepoints must be completed within a range of ± 10 days except for the 12-week, 6-month and optional 12-month timepoints
3 12-week and 6-month evaluations must be completed within a range of ± 14 days
4 12-week evaluation may be completed at either home institution or at the NIH Clinical Center; if performed at home institution, a physical exam is optional
5 optional 12-month off-study evaluation may be completed within a range of ± 30 days
6 Neurodevelopmental testing for pediatric patients (if previously performed at baseline) and specialized laboratory testing should be performed at the 3-month landmark if the 
12-week evaluations are performed at the NIH Clinical Center
7 May use screening results if obtained within 7 days of consent 
8 not required if already performed elsewhere and records available
9 at PI’s discretion if indicated
10 stained for standard morphologic analysis and quantitation of cellularity with hematoxylin and eosin, and special stains to assess iron, reticulin and collagen, primitive stem 
and progenitor cells via CD34 immunohistochemistry, and other lineage-specific or special stains as indicated to classify any abnormalities
11 MRI will be omitted if unable to be performed due to patient age, size, or intolerance; this will not be reported as a deviation, but will be noted in the medical record
12 only adult subjects 18 years and older who read English or Spanish will complete the survey
O recommended, but not required


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PI: David J. Young, M.D., Ph.D.
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Table 15: Schedule of Activities (Extended phase, beginning after 6 months of treatment)
Visit/ Time Point
Monthly
(±10 days)
Every 6 
Months 
(±30 days)
Every 12 
months
(±60 days)
Off study 
(optional)
(±30 days)
Clinical Assessments
Interval medical history
X1
X
X
Physical examination
X1
X
X
Neurodevelopmental assessment
X2
Pediatric consult
X2,3
X2,3
Laboratory Evaluations
Complete blood count with differential
X4
X4
X4
X
Peripheral blood smear
X1
X1
X
Reticulocyte count
X3
X3
X3
X
Hemoglobin F quantification
X
X
X
Erythrocyte adenosine deaminase
X
X
ALT, AST, Total Bilirubin, or Direct Bilirubin
X3
Hepatic panel:
Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin
X
X
X
Mineral panel: Phosphorus, Magnesium, Albumin, and Calcium
X
Acute care panel: Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen
X
X
X
Total Protein
X
CK
X
Uric acid
X
LDH
X
Pregnancy test
X3
X3
Ferritin
X4
X1
X1
Iron panel:
ferritin, transferrin, % saturation, total serum iron
XO
X1
X1
X
Metals: copper and zinc levels
X
X
Research Blood
X1
X1
X
24-hour urine collection to determine the total iron
X1,2
X1,2
X2


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PI: David J. Young, M.D., Ph.D.
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Procedures
Bone marrow aspiration and core biopsy5
X1
X1
X
Bone marrow chromosomal analysis via standard cytogenetic techniques
X1
X1
X
MRI (T2* liver iron concentration)6
X7
X7
Research Testing and Assessments
HRQL survey administration
X1
X1
Document Drug Accountability
X
X
1 per section 6.5.2, only every 12 months ± 60 days for robust responders who discontinue eltrombopag
2 at PI’s discretion 
3 per section 6.5.2, not required for robust responders who discontinue eltrombopag
4 per section 6.5.2, monthly (± 10 days) for 6 months and then every 3 months (± 30 days) for robust responders who discontinue eltrombopag
5 stained for standard morphologic analysis and quantitation of cellularity with hematoxylin and eosin, and special stains to assess iron, reticulin and collagen, primitive stem and 
progenitor cells via CD34 immunohistochemistry, and other lineage-specific or special stains as indicated to classify any abnormalities
6 MRI will be omitted if unable to be performed due to patient age, size, or intolerance; this will not be reported as a deviation, but will be noted in the medical record
7 imaging performed at first 6-month follow-up during extended phase, and then annually thereafter while on eltrombopag (see section 6.5) if deemed necessary by the PI
O recommended, but not required


Page 97 of 97
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APPENDIX B: Collection of samples for PK Assessments
Subjects will have PK assessments at the landmark 6-month study visit. Subject must have 
received once daily eltrombopag for at least 7 days prior to this visit (i.e., be at PK steady-state 
with no recent dose interruptions). If a subject is not currently receiving eltrombopag at the time 
of this visit (because of a dose interruption) or eltrombopag has been reinitiated after a dose 
interruption within the 7 days prior to this visit, PK assessments will not be obtained. The 
eltrombopag dosing history for the 2 weeks prior to the PK visit will be recorded (any dose 
interruptions, actual dose administered).
Blood samples (2 mL) for PK analysis will be collected in K2EDTA-containing tubes. One sample 
will be collected at each of the following times: within 30 min prior to eltrombopag dosing (pre-
dose sample), and at 2, 4, 6, and 8 h after eltrombopag dosing. An optional sample will be 
collected 24 h post-dose, prior to administration of eltrombopag the next day. 
Record the date, time, and amount (in mg) of the dose administered after the pre-dose PK 
sample. Collect each whole blood PK sample as close as possible to the planned time relative to 
dosing. Record the actual date and time that each sample was collected. 
If a cannula is used, the cannula will be inserted into an arm vein within sufficient time prior to 
dosing, will be kept patent with normal saline and will be removed after the last blood sample is 
collected or earlier if the subject requests. In order to avoid artificial dilution of the PK sample by 
the saline, 0.5-1mL of whole blood will be collected and discarded before each PK sample is 
collected. 
PK Sample Processing and Storage 
Each PK samples will be gently mixed by inversion 8 to 10 times (do not shake). Place the 
samples on ice immediately after collection. Within 1 hour of sample collection, the samples will 
be centrifuged in a refrigerated (2°C to 8°C) centrifuge at 1500 RPM for 10 minutes. The 
resulting plasma will be transferred into a properly-labeled polypropylene tube. Immediately, 
place the plasma samples upright in a -20°C freezer and retain the samples in the freezer until 
they are shipped for analysis. 
Shipping Instructions 
Samples should be shipped only on Monday, Tuesday, or Wednesday, not less often than 
every 2 months. Samples must be shipped on dry ice via overnight courier to:
LiMajor Pittman PPD 
2246 Dabney Road 
Richmond VA, 23230, USA 
Tel: (804) 977-8017
e-mail: limajor.pittman@ppdi.com

ICF_000.pdf: 
Informed Consent Cover Page for FDAAA consent posting:  
 
Official Title: 
 
Treatment of refractory Diamond-Blackfan anemia with eltrombopag 
NCT number: 
 
NCT04269889 
Document Type:  
Informed Consent Form  
Document Date: 
03/24/2022 
 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 1 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: David J. Young M.D., Ph.D.
STUDY TITLE: Treatment of refractory Diamond-Blackfan anemia with eltrombopag
STUDY SITE: NIH Clinical Research Center, Bethesda, MD
Cohort: Standard
Consent Version: March 23, 2022
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
David J. Young, M.D., Ph.D.
david.young2@nih.gov
301-827-7823
Research Nurse:
Ivana Darden, R.N.
ivana.darden@nih.gov
301-827-2988
KEY INFORMATION ABOUT THIS RESEARCH
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you make 
a decision can be found in other sections of the document. Taking part in research at the NIH is 
your choice.
You are being asked to participate in a research study sponsored by the National Heart, Lung, 
and Blood Institute at the National Institutes of Health because you have been identified as 
having Diamond-Blackfan anemia (DBA). Diamond-Blackfan anemia is often treated with 
steroids, often at high doses, to increase the number of oxygen-carrying cells (red blood cells or 
erythrocytes) in your blood. However, in your case, your doctors have determined that:

steroids have not been effective for you, or

the side effects of steroids are making it difficult or dangerous to continue, or

your disease has returned even though it had responded previously.
For you, and patients like you, we are examining whether a drug called eltrombopag (brand 
name Promacta®) can increase your blood counts, allowing you to come off of or remain off of 
steroids, while requiring fewer or no blood transfusions.
Eltrombopag is a drug that was developed for patients with low numbers of another blood 
component: platelets. It was originally designed to mimic a protein called thrombopoietin 
(TPO). TPO is a naturally found in the body and stimulates the body to make more platelets 
when they are low. It has proven safe and effective in increasing the number of platelets for 
patients with low counts due to other conditions such as chronic hepatitis C or chronic immune 
thrombocytopenia purpura (ITP), an autoimmune disorder in which patients have chronically 
low platelet counts.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 2 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Studies have since found that in aplastic anemia, eltrombopag increases the number of other 
blood cells including the red blood cells that are also low in Diamond-Blackfan anemia. As a 
result, the U.S. Food and Drug Administration (FDA) has also approved eltrombopag as part of 
the therapy for treating severe aplastic anemia. Like Diamond-Blackfan anemia, aplastic anemia 
is a failure of the bone marrow to produce blood cells, but unlike Diamond-Blackfan anemia, 
which is present at birth and can be passed from parents to their children, aplastic anemia is 
usually acquired later in life; however, in a recent trial of eltrombopag in a moderate aplastic 
anemia, a patient with Diamond-Blackfan anemia responded to eltrombopag.
The purpose of this study is to test whether the eltrombopag will be safe and effective in treating 
Diamond-Blackfan anemia in general, especially for patients like you for whom steroid therapy 
has not provided a durable treatment. It is also unclear how eltrombopag improves counts in 
Diamond-Blackfan anemia. Therefore, it is secondary goal of this study to learn how 
eltrombopag functions in Diamond-Blackfan anemia.
During this study, you will take eltrombopag once a day, every day for six (6) months 
(24 weeks). During that time, you must have your blood drawn once every two (2) weeks 
(14 days) to monitor your body’s response to eltrombopag and monitor for signs of side effects. 
These can be done at your home institution or at the NIH. You will need to return to the NIH at 
the end of the 6 months for blood tests, bone marrow biopsies and MRI scans to see how your 
bone marrow has responded to eltrombopag. This visit will take place at the NIH Clinical Center. 
Most visits, including testing, are performed within one day. Occasionally, especially for 
pediatric patients, the visit takes two days. The study staff will provide specific dates and times 
for your study visits and tests.
You may continue taking most medications that were prescribed before you started the study. 
Because these other medicines might interact with the study drugs, we ask that you tell us about 
all of your medications or changes in the medications you take, including prescription drugs, 
over-the-counter products, vitamins, and herbal supplements. We will inform you of any 
medications that you will need to stop while you are on eltrombopag.
If you have any new and concerning systemic symptoms (e.g. fevers, rigors, severe fatigue), 
respiratory symptoms (e.g. shortness of breath, persistent cough, chest pain), or gastrointestinal 
symptoms (e.g. diarrhea or blood in your stool), you should immediately notify your doctor for 
further evaluation.
Your participation will continue for at least six months at which point we will decide if you have 
demonstrated a response, including:

increase in blood counts from your baseline, or

fewer transfusions required.
If you do respond to and tolerate eltrombopag, you will be offered the opportunity to continue 
on an extended trial of eltrombopag, lasting for up to an additional three (3) years, unless you 
decide that you no longer want to be in this study, or the Sponsor decides to stop or interrupt the 
study.
The possible benefit from this study is that eltrombopag may help treat your Diamond-Blackfan 
anemia. If you decide to participate in this study, your health will be monitored very closely 
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 3 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
which may provide a benefit to you. By being in this study, you will give doctors more 
information about how well eltrombopag works. It may help doctors understand your condition 
better and may help future patients with Diamond-Blackfan anemia.
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could choose to be treated by your home 
health care provider. Treatments include repeat trials of high-dose steroids, chronic transfusions, 
and hematopoietic stem cell transplant (sometime referred to as a bone marrow transplant or 
cord blood transplant). Alternative experimental therapies include high-dose leucine. 
Sotatercept and luspatercept are engineered proteins that disrupt the GDF11 pathway to increase 
red blood cell production. Trifluoperazine (Stelazine®) is an antipsychotic medication that may 
have activity in Diamond-Blackfan anemia. These, and other alternative experimental therapies, 
may be available at other research centers. You cannot participate in this study at the same time 
you are on other experimental treatments for Diamond-Blackfan anemia.
The remaining document will now describe more about the research study.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
For parents or guardians consenting for their children: If the individual being enrolled is a minor 
then the term “you” refers to “you and/or your child” throughout the remainder of this document.
For caregivers consenting on behalf of people unable to give consent: If the individual being 
asked to participate in this research study is not able to give consent to be in this study, you are 
being asked to give permission for this person as their decision-maker. The term “you” refers to 
you as the decision-maker and/or the individual being asked to participate in this research, 
throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this research study is to examine the safety and efficacy 
of eltrombopag in treating patients with Diamond-Blackfan anemia who have not responded to 
previous therapies such as steroids, or who were unable to tolerate those therapies. Eltrombopag 
has been approved by the U.S. Food and Drug Administration (FDA) to treat severe aplastic 
anemia in combination with other drugs or for patients who had previously received those drugs 
alone without a response. Eltrombopag has also been approved by the FDA to treat patients with 
chronically low platelet counts. Clinical trials which have shown that eltrombopag to be effective 
and safe in patients with moderate aplastic anemia have included patients with Diamond-Blackfan 
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anemia, but eltrombopag has not been specifically approved for efficacy and safety in this patient 
population.
We are asking you to join this research study because you have been diagnosed with Diamond-
Blackfan anemia, and steroid therapy, whether it has worked for you in the past or not, is no longer 
considered the best therapy for you.
WHAT WILL HAPPEN DURING THE STUDY?
Eltrombopag (also called Promacta®):
You will take eltrombopag pills by mouth once a day for 24 weeks.
Before you take the first dose, you will need to have lab tests repeated within 7 days. If you are a 
female of childbearing potential, you must have the pregnancy test repeated within 7 days of your 
first dose (pregnancy and testing are discussed in detail below).
While you are taking eltrombopag, we will monitor you closely for side effects. You will need to 
have bloods tests performed every 2 weeks while you are taking eltrombopag. The tests can be 
done here at the NIH or by your home physician. We will also monitor you by occasional visits 
with physical examinations and procedures (no more than twice a year). Based on any side effects 
that you report or your laboratory results, we may change your eltrombopag dose. This may mean 
lowering your dose or temporarily stopping it. This may also mean stopping it completely, 
depending on what is in your best interest. The tests and visit schedule are explained in more detail 
below.
Extended access to study drug. There are currently no guidelines for length of therapy with 
eltrombopag. The limited experience we have for treating patients with Diamond-Blackfan anemia 
and related diseases with eltrombopag suggests that patients may benefit from extended treatment. 
If you continue to show benefit from the eltrombopag at the end of the 24 weeks of therapy, you 
will be allowed to continue through the extended access part of the trial.
You will continue taking eltrombopag until your blood cell counts improve to “robust” levels 
(hemoglobin level of 10 g/dL without transfusions) or no further response is expected. We will 
then follow your counts until 3 years after you discontinued eltrombopag. During this time, 
eltrombopag can be re-started if your counts fall to low levels again. The maximum time 
eltrombopag will be provided after signing the consent for the extended access part of the study is 
3 years. After study completion, the research team will help coordinate continuing follow-up care 
with your referring physician.
Permitted standard of care for your disease (not investigational):

Transfusions: You will receive blood and/or platelets if you need them

Women: Estrogens or combination oral birth control pills as needed for uterine bleeding

Iron chelating agents: If you have high iron (hemochromatosis), chelating agents such as 
deferasirox (Exjade/Jadenu) should be continued while you are on eltrombopag. We will 
monitor your iron levels, and help you decide if you should stop your chelating agent if 
your iron level is falling.
Non-permitted medications: The following treatments are not allowed to be taken during this 
study (they could interfere with eltrombopag):
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
Romiplostim (N-Plate), or any related agents known as thrombopoietin receptor agonists

Androgens (i.e. danazol and oxymetholone)

IL-11 (Neumega)

Investigational/non-marketed drugs or herbal supplements (unless the Investigator decides 
the medication will not interfere with the study drug)
Steroids
You cannot take steroids for anemia while on study. If you take steroids for a condition known as 
adrenal insufficiency (also called “replacement dosing” or “physiologic replacement”) you should 
continue these. The research team will review your steroid management to make sure that this will 
not interfere with eltrombopag and prevent you from participating in this study.
Permitted medications
You may continue taking any medications prescribed before you started the study, as long as they 
are not related to your low blood counts. Your medicines might interact with the study drug 
(eltrombopag). This is why we ask that you tell us about all of your medications or changes in the 
medications you take. This includes prescription drugs, over-the-counter products, vitamins, and 
herbal supplements. If you are taking rosuvastatin (Crestor) to lower blood lipids, we may need to 
reduce your dose of eltrombopag and carefully monitor you.
Special instructions for eltrombopag

Timing in relation to food: When eltrombopag is taken with a meal containing high fat 
or calcium, the amount of eltrombopag absorbed is decreased. Therefore, eltrombopag 
should be taken on an empty stomach (1 hour before or 2 hours after a meal).

Timing in relation to antacids: When eltrombopag is taken with antacids, the amount of 
eltrombopag in the blood is decreased.  Take eltrombopag at least 4 hours before or after 
products containing aluminum, calcium, magnesium, iron, selenium, and zinc.  Examples 
of these products include antacids, mineral supplements, and dairy products.

Storing the study drug: Store at room temperature.  Room temperature is between 59°F 
to 86°F.  It must be stored out of the reach of children.

Early stopping of eltrombopag: We ask that you inform us immediately if you stop taking 
the study drug (eltrombopag) for any reason.
What procedures are involved in this research study?
If you agree to be in this study, you will be asked to complete all procedures before you take and 
as long as you remain on study drug. This means visits can occur with your NIH doctors or at your 
home doctor’s office every two weeks. You will have to come to the NIH six (6) months after 
starting eltrombopag.
You will be responsible for following the NIH research team’s instructions. You are also 
responsible for telling them of any changes in your health and if you decide to stop taking the study 
drug.
While you are taking eltrombopag please fax the following to the study coordinator: Ivana Darden, 
R.N. at 301-402-3088:

Results of lab tests performed outside of the NIH
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
Transfusion records

Any medical notes your physician writes about you when see her or him

Records from any hospitalizations, emergency room visits, or urgent care visits
What evaluations are done before you take your first dose of eltrombopag?
You must have the following tests done 7 days before your first dose.  You may have them done 
here at the NIH or at your physician’s office.

A blood sample (1-2 teaspoons) to run tests to evaluate the make-up of your blood.

For anyone of childbearing potential, a pregnancy test (urine or blood)
If these tests are not done at the NIH, please send a copy of the results to the research nurse.
What evaluations are done every two weeks while you are taking eltrombopag?
During your first six (6) months on eltrombopag, you must have the following tests done every 14 
days (between 7 and 21 days). You may have them done here at the NIH or at your physician’s 
office. We will accept tests up to seven (7) days before or after the expected date. Tests can be 
done more often if your doctor thinks they are necessary, but those outside of this window will not 
count towards the study requirements.

A blood sample (1-2 teaspoons) to run tests to evaluate the make-up of your blood.
If these tests are not done at the NIH, please send a copy of the results to the research nurse.
What evaluations are done at month 3 and 6 while you are taking eltrombopag?
You will need a comprehensive visit at 3 months and 6 months after you have started taking 
eltrombopag. The six (6) month visit must be at the NIH. The three (3) month visit may be at your 
home institution or at the NIH. During these visits, the following evaluations will be done:

A clinical assessment, which will include a brief history with questions about how you are 
feeling, a physical exam, and measurement of your blood pressure, pulse, temperature, 
respirations (vital signs)

A review of your medications

A blood sample (1-2 teaspoons)

A repeat pregnancy test in women of childbearing potential
If the 3-month visit is not done at the NIH, we will ask you to send a copy of the results to the 
research nurse, and we will contact you by phone or email to assess how you are doing.
At the 6-month visit at the NIH, you will also undergo:

A bone marrow biopsy test

A questionnaire about your quality of life

A neurodevelopmental test, if you are a pediatric patient under 18 years of age

An MRI of your liver to measure the iron concentration

A 24-hour urine collection may be performed
If you are not responding to eltrombopag at the month 6 visit, you will be taken off study drug.  If 
you are taken off study drug, we would like you to come back to the NIH in 6 months.
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What evaluations are done at the optional visit after you stop taking eltrombopag?
The following will be done.

A clinical assessment, which will include a brief history with questions about how you are 
feeling, a physical exam, and measurement of vital signs

A blood sample (1-2 teaspoons)

A series of blood samples (before your morning dose and then 2, 4, 6, and 8 hours after the 
dose to measure the amount of eltrombopag in your blood).  A total of 2 teaspoons will be 
drawn.  This test will only be done once, either at your 3-month visit or at your 6-month 
visit.

A bone marrow biopsy test

A questionnaire about your quality of life

An MRI of your liver to measure the iron concentration
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for up to three (3) years 
and six (6) months. Initially, we will ask you to take the eltrombopag for 24 weeks (6 months).  If 
we see an improvement in your blood cell counts, you will be asked to participate in the extended 
access part of the study.  You will continue taking eltrombopag after the 6-month evaluation.
After 24 weeks of treatment, if there is no improvement in your blood cell counts, we will ask that 
you come back for a follow-up visit.  This will occur 6 months after your last dose of eltrombopag.  
This visit is optional.
During the initial 6 months of your treatment, you will need to have blood drawn at your home 
institute every 2 weeks. We will request that you have at least one visit with your home provider 
or at the NIH after taking eltrombopag for 12 weeks (3 months). If you continue to take 
eltrombopag after the initial 6 months, you will need bloodwork once a month for the next six (6) 
months, and then every 3 months while you remain on eltrombopag. During that time, you will 
need to come to the NIH every six months. After you come off of eltrombopag, we will continue 
to monitor you at the NIH for up to three years.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 25 eligible people participate in this study at the NIH.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
Risks related to eltrombopag
The following possible risks are reported in adults taking eltrombopag for disease other than 
Diamond-Blackfan anemia. The diseases include chronic immune thrombocytopenic purpura 
(ITP), chronic hepatitis C, and severe aplastic anemia (SAA).  The patients received a maximum 
dose between 50 to 150 mg per day.
Progression of underlying disease or progression to a new myelodysplastic syndrome (MDS) and/ 
or new acute myelogenous leukemia (AML, a type of blood cancer) has occurred in patients with 
ITP (immune thrombocytopenia purpura), MDS, AML and SAA (severe aplastic anemia). In some 
patients with these diseases who are treated with eltrombopag, changes in bone marrow cells 
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occurred. In some cases, this may indicate a progression to cancer. The role of eltrombopag in 
these changes is not known. These changes have also been seen with other drugs in the same class 
of compounds as eltrombopag. During this study, we examine your blood and bone marrow 
periodically for these changes.
Severe rash: There is a risk that you may develop a severe rash that may require hospitalization 
and discontinuation of eltrombopag.
Boxed Warning:
RISK FOR 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 (decompensation 
means the liver can no longer repair itself).
Additional Serious Side Effects include the following:
Liver problems: Eltrombopag may damage your liver and cause serious illness and death. The 
research team will order blood tests to check your liver function before you start taking 
eltrombopag and during treatment with eltrombopag. In some cases, eltrombopag treatment 
may need to be stopped. Tell the research team right away if you have any of these signs 
and symptoms of liver problems:

Yellowing of the skin or the whites of the eyes (jaundice),

Unusual darkening of the urine,

Unusual tiredness, or

Pain in the right upper stomach area.
High platelet counts and higher chance for blood clots. Your risk of getting a blood clot is 
increased if your platelet count is too high during treatment with eltrombopag. Your risk of getting 
a blood clot may also be increased during treatment with eltrombopag if you have normal or low 
platelet counts. You may have severe problems or die from some forms of blood clots, such as 
clots that travel to the lungs or that cause heart attacks or strokes. The doctor will check your blood 
platelet counts and change your dose or stop eltrombopag if your platelet counts get too high. Tell 
your doctor right away if you have signs and symptoms of a blood clot in the leg, such as swelling, 
pain, or tenderness in your leg.
The most common side effects of eltrombopag in people with diseases other than Diamond-
Blackfan anemia include:
For people with severe aplastic anemia (SAA):

Anemia (low red blood cell count) (Very common – more than 10% of patients)

Nausea, diarrhea, stomach pain (very common - more than 10% of patients) 

Fatigue, dizziness, fever, fevers with very low white blood cells (febrile neutropenia) (very 
common - more than 10% of patients)

Cough, runny nose, shortness of breath, sore throat (common - less than 10% of patients)

Headache (very common - more than 10% of patients)

Pain in arms or legs, muscle spasms, joint pain (very common - more than 10% of patients)

Skin redness, increased liver function tests (very common - more than 10% of patients)
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
Small blood vessel problem that result in kidney failure (rare – less than 0.1% of patients)
For adult patients with Idiopathic Thrombocytopenia (ITP):

Nausea, diarrhea (very common - more than 10% of patients)

Vomiting, dry mouth (common - less than 10% of patients)

Muscle aches, back pain, chest pain, joint pain, arm pain, leg pain (common – less than 
10% of patients)

Abnormal skin sensations, such as tingling, itching, burning, rash, hair loss (common – less 
than 10% of patients)

Abnormal liver function test results (common – 5% of patients)

Infections (throat, urinary tract) (common – up to 10% of patients)

Headache (10% of patients)

Small blood vessel problem that result in kidney failure (rare – less than 0.1% of patients)

Drug Induced Liver injury (uncommon – less than 1% of patients)
For children (ages 1 to 17 years old) with ITP:

Headache (very common – more than 10% of patients)

Infections that result in a head or chest cold (very common – more than 10% of patients)

Infections that result in a runny nose, stuffy nose, sneezing (common – up to 10% of 
patients)

Stomach pain, diarrhea, tooth pain (common – up to 10% of patients)

Fever (common – up to 10% of patients)

Cough, sore throat, runny nose, stuffy nose (common – less than 10% of patients)

Small blood vessel problem that results in kidney failure (rare – less than 0.1% of patients)
Unknown side effects: Treatment with eltrombopag may involve risks that are currently unknown. 
If significant new findings develop during the study, we will report them to you as soon as possible. 
New information might affect your willingness to participate in this study.
Risks related to concurrent use of other medications: To avoid the possibility of unknown 
effects from combining therapies, you cannot take medications for Diamond-Blackfan anemia 
other than those allowed by the study. The research team will discuss with you your current 
treatments for Diamond-Blackfan anemia before you start the study.
Risks related to blood tests
Side effects of blood sampling include pain, bleeding, and/or bruising in the area where the blood 
was drawn, lightheadedness, or, rarely, fainting due to temporary lowering of blood pressure.  If 
you feel dizzy, we will ask you to lie down for a few minutes to avoid falling and hurting yourself. 
Infection at the blood-drawing site could also occur.
Risks related to bone marrow biopsy
Because Diamond-Blackfan anemia affects your blood, we will need to take samples of your bone 
marrow (where blood is produced). We will numb the area above your hip bone with a local 
anesthetic. The anesthetic can cause some temporary stinging and burning. When the area is numb, 
we will remove a sample of the bone and marrow with a thin needle. You may feel a pulling 
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sensation and discomfort as the marrow is withdrawn. The amount of marrow taken is very small 
and will not further compromise your body's ability to form blood. A pathologist will read the 
sample to confirm your diagnosis. The only potential complications of this procedure are bleeding 
at the site and local infection. Both are very rare. Bleeding can be stopped by applying local 
pressure, and an infection can be treated with antibiotics.
Risks related to MRI scans
Having an MRI scan may mean some added discomfort for you. In particular, you may be bothered 
by feelings of claustrophobia when you are inside the scanner, or by lying in one position for a 
long time. MRI scanners are often loud, but you will be provided with hearing protection. The 
scans, as planned will typically take 15-20 minutes, but may take longer. If you experience 
significant discomfort, we can provide calming medications to help with anxiety. For some 
patients, especially children, it may be necessary to use sedation (such sedation would be covered 
by a separate consent form). The presence of metal such as piercings or jewelry can cause harm or 
injury when in the MRI scanner, including, but not limited to burns. You will be screened for any 
metal before all scans, and many medical implants are MRI-safe, but notify the research team, 
your doctor, and the technologist performing the scan if you have any metal implants. We do not 
plan to use contrast for these scans.
Risks related to genetic testing
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond.
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them.
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
What are the risks related to pregnancy?
The effects of eltrombopag upon pregnancy and the developing fetus are not known. Therefore, if 
you are pregnant, breastfeeding, or plan to become pregnant during the time you would be enrolled 
on this study (the next four to six years), you cannot participate.
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We will require all enrolled subjects who are capable of becoming pregnant to have a pregnancy 
test before beginning this study and intermittently throughout their time on the study, regardless 
of sexual activity, martial or relationship status, or the use of contraceptive methods. You must use 
effective birth control methods and try not to become pregnant while taking eltrombopag on this 
study and continuing until at least 30 days after the last dose eltrombopag. “Effective birth control 
methods” include:

Total abstinence (no sexual intercourse).

Surgical sterilization including tubal ligation (tubes tied) or hysterectomy (removal of 
uterus or womb) in women or a vasectomy in men.

Oral contraceptives (birth control pills), intrauterine devices (IUD), implantable or 
injectable contraceptives in combination with barrier methods (such as a condom or 
diaphragm) used with a spermicide.

Barrier methods (such as a condom or diaphragm) used with a spermicide.
The contraception methods described above may not protect against HIV infection (AIDS) and 
other sexually transmitted diseases. If you need more information about this, please ask your study 
doctor.
You must tell the study doctor if your birth control method fails while you are in the study. If you 
think or know you have become pregnant while participating in this research study, please contact 
the research team member identified at the top of this document as soon as possible. If you plan to 
become pregnant in the future, you should wait 30 days from the last dose of eltrombopag. Please 
discuss this with the research team.
If you are a sexually active person with a partner capable of becoming pregnant, it is important 
that your partner not become pregnant during your participation in this study. There may be 
unknown risks to a fetus or risks to your partner we did not anticipate. You and your partner must 
agree to use effective birth control methods listed above if you want to take part in this study. If 
you think your partner has become pregnant during your participation in this study, please contact 
the research team member identified at the top of this document as soon as possible.  If you and 
your partner plan for your partner to become pregnant after your participation in this study, please 
discuss this with the study team.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study.
However, the goal of this study is to examine whether eltrombopag improves blood counts in 
patients with Diamond-Blackfan anemia, and as such eltrombopag may help to treat your anemia, 
reducing or even eliminating blood transfusions, reducing your exposure to other medications such 
as steroids, and potentially delaying or even eliminating the need for hematopoietic stem cell 
transplantation in the future.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because it will help doctors understand 
how eltrombopag affects Diamond-Blackfan anemia. It will also give doctors new and better 
information into how the changes seen in Diamond-Blackfan anemia cause the anemia and how it 
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responds to drugs such as eltrombopag. Even if this trial is unsuccessful, the data we gain may 
help doctors design future drugs and trials to treat Diamond-Blackfan anemia.
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, we will discuss the following standard alternative 
treatments to Diamond-Blackfan anemia, which, depending on your age, disease status, iron 
levels, and the availability of stem cell donor, may be available and appropriate for your disease 
including:

Transfusions of red blood cells

Steroid therapy

Bone marrow transplantation

Other experimental therapies

No therapy
Note, although eltrombopag is commercially available, it is not currently indicated for use in 
Diamond-Blackfan anemia, therefore it is generally not available to patients with Diamond-
Blackfan anemia except as part of trials such as this one. Choosing not to participate in this trial 
will not affect your ability to participate in other clinical trials at the NIH and NHLBI, including 
any future trials with eltrombopag or related agents.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we will 
get in touch with you to explain what we have learned. This may be information we have learned 
while doing this study here at the NIH or information we have learned from other scientists doing 
similar research in other places. If this happens, the research team will tell you about it and talk 
with you about whether you want to continue in the study. If you decide to continue in the study, 
we will ask you to sign an updated consent form.
Return of research results
Clinically relevant research results will not be shared with you. This does not include any results 
that are collected as part of your routine care. Any clinically actionable genetic results will be 
shared with you, with the option of discussing these results with one of our geneticists.
EARLY WITHDRAWAL FROM THE STUDY
Your participation in this study is voluntary, and you may stop at any time. It is possible that after 
receiving new information about the treatment, the research team will consider it to be in your best 
interest to withdraw from the study. A member of the research team will explain the reasons and 
arrange for your care to continue.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 13 of 19
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Your participation on this research study may end for the following reasons:

You have side effects that make it unsafe for to keep taking the drug

Your blood counts are not improving

You become pregnant

The research team decides that it is not in your best interest to continue on the study
If at the end of the study you are having any side effects related to the study drug, you might be 
asked to return for additional tests until the side effects have gone away.
The principal investigator of this study (David Young, M.D., Ph.D.), the medically-responsible 
sponsor of the trial (Cynthia Dunbar, M.D.), the Institutional Review Board (IRB), the Food and 
Drug Administration, or Novartis (supplier of the study drug) may stop this study at any time, for 
any reason, without your consent. For safety reasons, the Data Safety Monitoring Board may also 
recommend stopping this study without your consent. You would be told of that new information.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved for use in other research studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding Diamond-Blackfan anemia, or other 
diseases or conditions. This could include studies to develop other research tests, treatments, 
drugs, or devices, that may lead to development of a commercial product by the NIH and/or its 
research or commercial partners. There are no plans to provide financial compensation to you if 
this happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will your specimens or data be shared for use in other research studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you. They may be doing research in areas similar to this research or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 14 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them.
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not.  If you do not wish to have your data placed in this 
database, you should not enroll in this study.
Will your genomic data be shared outside of this study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex. If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 15 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH until they are no longer of a scientific value, 
at which time they will be destroyed.
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your data or 
samples.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study.
Will you receive reimbursement or direct payment by NIH as part of your participation?
This study offers reimbursement or payment for travel, lodging or meals while participating in the 
research. The amount, if any, is guided by NIH policies and guidelines.
Will taking part in this research study cost you anything?
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. All major procedures (bone marrow tests, 
research tests, MRI, etc.) and study drugs are included under this; however, you or your insurance 
may be charged for bloodwork not performed at the NIH Clinical Center.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
Novartis Pharmaceuticals is providing eltrombopag for this study to NIH without charge. No NIH 
employee involved in this study receives any payment or other benefits from Novartis for this trial. 
Novartis has provided Dr. Cynthia Dunbar and Dr. Neal Young funding for prior trials separate 
from this trial.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 16 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor the National Heart, Lung, and Blood Institute (NHLBI) Office of 
Clinical Director (OCD) at the NIH or their agent(s)

Qualified representatives from Novartis Pharmaceuticals Corporation, the pharmaceutical 
company who produces eltrombopag.

Novartis’ authorized agents

Governmental agencies in other countries where the study drug may be considered for 
approval
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you.
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);
3. is for other research;
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 17 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
4. is disclosed with your consent.
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, David J. 
Young, M.D., Ph.D., email: david.young2@nih.gov, phone: 301-827-7823. You may also 
contact the Study Coordinator: Ivana Darden, R.N., email: ivana.darden@nih.gov, phone: 301-
827-2988. You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or 
the NIH Office of IRB Operations at 301-402-3713, if you have a research-related complaint or 
concern.
CONSENT DOCUMENT
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 18 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study.
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Signature of Parent/Guardian (as applicable)
Print Name of Parent/Guardian
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process with a non-English speaking subject and this English consent form has been approved 
by the IRB for use as the basis of translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/23/2022
Page 19 of 19
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 20H0021
IRB APPROVAL DATE: 03/24/2022