Treatment of Refractory Diamond-Blackfan Anemia With Eltrombopag
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04269889|
Recruitment Status : Recruiting
First Posted : February 17, 2020
Last Update Posted : September 9, 2021
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.
To study the safety and efficacy of eltrombopag in people with DBA who have not responded to steroids or could not take them.
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
Participants will be screened with:
Medical and medicine history
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.
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:
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....
|Condition or disease||Intervention/treatment||Phase|
|Anemia, Diamond-Blackfan||Drug: Eltrombopag||Phase 1 Phase 2|
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).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Treatment of Refractory Diamond-Blackfan Anemia With Eltrombopag|
|Actual Study Start Date :||December 1, 2020|
|Estimated Primary Completion Date :||June 30, 2023|
|Estimated Study Completion Date :||June 30, 2027|
Experimental: Treatment arm
Diamond-Blackfan anemia patients
150 mg/day starting dose (titration and adjustments for age and ethnicity)
- Proportion of drug responders [ Time Frame: 6 months (24 weeks +/- 14 days) ]Proportion of drug responders as measured by International Working Group criteria
- Drug toxicity profile [ Time Frame: 6 months (24 weeks +/- 14 days) ]Toxicity profile as measured using the CTCAE criteria
- Rates of relapse and survival according to clinical outcomes [ Time Frame: Every 6 Months ]Rates of relapse and survival according to clinical outcomes
- Rates of clonal evolution as measured by karyotypic changes [ Time Frame: Every 6 Months ]Rates of clonal evolution as measured by karyotypic changes
- Platelet count as measured by serial CBC assessments at landmark intervals [ Time Frame: Month 3 & 6 ]Platelet count as measured by serial CBC assessments
- Neurodevelopment in pediatric patients as measured by validated neurodevelopmental measurements [ Time Frame: At baseline & Month 6 ]Neurodevelopment in pediatric patients as measured by validated neurodevelopmental measurements
- Long-term safety of drug [ Time Frame: Up to 3 years ]Toxicity profile as measured using the CTCAE criteria.
- Iron overload as measured by serial ferritin levels, T2* MRI measurements and bone marrow iron staining [ Time Frame: Month 3 & 6 ]Iron overload as measured by serial ferritin levels, T2* MRI measurements and bone marrow iron staining
- Health-related quality-of-life as measured by patient/guardian-completed HRQL [ Time Frame: Every 6 Months ]Health-related quality-of-life as measured by patient/guardian-completed HRQL
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04269889
|Contact: Evette N Barranta||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||David J Young, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|