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Anemia, Diamond-BlackfanPhase 1/2NCT04269889

Treatment of Refractory Diamond-Blackfan Anemia With Eltrombopag

A Phase 1/2 study testing Eltrombopag in people with Anemia, Diamond-Blackfan, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 2 years and older
Conditions the study is for
Anemia, Diamond-Blackfan
What is being tested?
Eltrombopag
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
1 siteUnited States
Study dates
1 Dec 2020to 16 Feb 2024
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • In order to be participate in this study, individuals must meet all of the following criteria:
  • 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.
  • Clinically-significant anemia as defined as either:
Show all 12Show fewer
  • 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
  • Relapsed and/or steroid-refractory or intolerant of systemic corticosteroids
  • Age greater than or equal to 2 years
  • Weight greater than or equal to 12 kilograms
  • 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

Who cannot join

  • 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.
  • Platelet count > 400,000 / microliter
  • Stage 4 or greater kidney disease as defined by creatinine > 2.5 mg/ dL or GFR < 30 mL/min/1.73 m(2)
  • --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 less than or equal to 45 mL/min/1.73 m(2)).
  • Direct bilirubin > 2.0 mg/ dL, including congenital abnormalities in the bilirubin level
  • SGOT (AST) or SGPT (ALT) > 5 times the upper limit of normal
Show all 39Show fewer
  • Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4 weeks prior to initiating eltrombopag.
  • --Physiologic steroid replacement for adrenal insufficiency or other similar conditions is not exclusive of trial participation
  • 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
  • Hypersensitivity to eltrombopag or its components
  • 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
  • Life expectancy of less than 3 months for any cause
  • Subjects with known liver cirrhosis in severity that would preclude tolerability of eltrombopag as evidenced by albumin < 3.5g/dL
  • History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
  • Recent myocardial infarction (within last 6 months),
  • Uncontrolled congestive heart failure,
  • Unstable angina (within last 6 months),
  • Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree AV block without a pacemaker.)
  • Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator
  • 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).
  • Known active or uncontrolled infections not adequately responding to appropriate therapy.
  • --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. HIV RNA viral load must be undetectable at the time of enrollment, and CD4 cell count must be greater than or equal to 200/microliter. 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.
  • Active malignancy or likelihood of recurrence of malignancies within 12 months
  • Evidence for MDS or AML as defined by WHO criteria.
  • Patients who have received chemotherapeutic treatment or other specific antineoplastic drugs or radiation therapy within 6 months of study entry
  • Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotrophin (b-hCG) pregnancy test) at screening or pre-dose on Day 1.
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 30 days after the last dose of eltrombopag. 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 child bearing potential.
  • 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.
  • History of thromboembolic events other than catheter-related thromboses
  • Active alcohol/drug abuse
  • 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
  • Unable to take investigational drug
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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.

Read more

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....

Read the 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).

Being tested
Eltrombopag
Keywords
Chelation, Ribosomopathy, Erythroid Aplasia, Iron Homeostasis, Hemoglobin Synthesis, Heme Synthesis
Medical subject headings
Anemia, Diamond-Blackfan, Anemia, Aplastic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EltrombopagDrug

    Also called EPAG

    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.

Study groups in NCT04269889
Study groupRoleWhat they receive
Refractory Diamond-Blackfan Anemia in EltrombopagExperimentalParticipants 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.
Receives: Drug: Eltrombopag

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Participants That Responded to Eltrombopag

    Participants that responded to Eltrombopag as defined by:

    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.

    Measured: 6 months (24 weeks +/- 14 days)

  2. Time (Weeks) to Response

    Time-to-response in weeks 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.

    Measured: 6 months (24 weeks +/- 14 days)

  3. Number of Adverse Events

    Number of Adverse Events

    Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as:

    Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living.

    Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.

    Grade 4 Life-threatening consequences; urgent intervention indicated.

    Measured: 6 months (24 weeks +/- 14 days)

Secondary outcomes (9)

  1. Number of Participants That Responded to Eltrombopag

    Number of Participants That Responded to Eltrombopag. As determined by the response to treatment, which will be assessed based on one or more of the following criteria:

    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.

    Measured: 3 Months

  2. Number of Participants With Robust Response to Eltrombopag

    Number of Participants with Robust Response to Eltrombopag regardless when it is achieved. Best response is defined as robust response or not robust response.

    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

    Measured: 3 Months, 6 Months, Up to 27 Months

  3. Median Change in Platelet Count

    Median Change in Platelet Count as measured by serial CBC assessments

    Measured: Baseline, 3 months

  4. Median Change Absolute Neutrophil Count

    Median Change Absolute Neutrophil Count as measured by serial CBC assessments

    Measured: Baseline, Month 3

  5. Number of Participants That Experienced Relapse

    Number of Participants that experienced Relapse during extension phase. Relapse is defined as no longer meeting response criteria.

    Response criteria is defined as: 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.

    Measured: 6 months up to 27 months

  6. Number of Participants That Experienced Clonal Evolution

    Number of participants that experienced clonal evolution according to cytogenetic, mutational or flow cytometric markers

    Measured: 6 Months and Up to 27 months

  7. Number of Adverse Events During the Extension Phase

    Number of Adverse Events

    Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as:

    Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living.

    Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.

    Grade 4 Life-threatening consequences; urgent intervention indicated.

    Measured: 6 months Up to 27 months

  8. Neurodevelopment in Pediatric Patients

    Neurodevelopment in pediatric patients as measured by validated neurodevelopmental measurements

    Measured: At baseline and Month 6

  9. Number of Participants With Iron Overload

    Number of participants with Iron overload. Iron overload as measured by serial ferritin levels, T2* MRI measurements and bone marrow iron staining

    Measured: Month 6

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2020
  2. Study start1 Dec 2020
  3. Primary completion16 Aug 2022
  4. Study completion16 Feb 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04269889
Sponsor's protocol ID
200021
Other IDs
20-H-0021
Status last verified
Nov 2024
First submitted
13 Feb 2020
Last updated
27 Apr 2025
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Eltrombopag in people with Anemia, Diamond-Blackfan, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Sep 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Participants That Responded to Eltrombopag (time frame: 6 months (24 weeks +/- 14 days)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04269889.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2025.

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