Eltrombopag & Cyclosporine in Children With Sever Aplastic Anemia

Eltrombopag Clinical Trial

— Eltroplastic  

Official title:

Randomized Clinical Trial of the Use of & Cyclosporine in Children With Sever Idiopathic Aplastic Anemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03243656
• Other study ID #: MAAhmed
• Status: Completed
• Phase: Phase 4
• Start date: December 20, 2017
• Est. completion date: January 5, 2020

Study information

• Verified date: January 2022
• Source: Assiut University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone marrow.but,It is very serious disease causing morbidity and mortality.

Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant number of patients have persistent cytopenias. Currently, the treatment of these patients is regular transfusion, which are expensive, inconvenient, and associated with serious side effects related to iron overload and transfusion.

Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site of thrombopoietin therefore it does not compete for binding with the native molecule. It promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote other hematopoietic stem cell as well as in thrombopoiesis .

Description:

Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone marrow.This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia) . The clinical consequences are anemia, usually with a requirement for frequent red blood cell transfusions, life-threatening bleeding from thrombocytopenia, and infection because of neutropenia. Bacterial and fungal infections are most common and are a significant cause of morbidity and mortality.

The incidence of acquired Aplastic anemia in Europe and North America is around two per million children per year . The incidence is 2-3 times higher in East Asia. There is no significant difference in incidence between males and females .

The pathogenesis of Aplastic anemia is complex and involves an abnormal hematopoietic microenvironment, hematopoietic stem cell/progenitor cell deficiencies and immunity disorders. The etiological basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment. The distinction between acquired and inherited disease may present a clinical challenge, Congenital or inherited causes of Aplastic anemia are responsible for at least 25% of children with this condition and for perhaps up to 10% of adults. Acquired causes of Aplastic anemia form (80%) of cases, include Idiopathic (> 80 %), Post-infectious 15% (particularly after hepatitis 9%, Epstein-Barr virus , human immune deficiency virus, parvovirus, and mycobacteria, Drug-induced and toxins (4%).

Definitive and potentially curative therapy with haematopoietic stem cell transplantation However, only a minority (30 %) of patients have a suitable donor. Immunosuppressive therapy with horse or rabbit antithymocyte globulin plus cyclosporine is the most commonly used alternative treatment in about two thirds of cases. Response is associated with a favorable long-term outlook. 30 -40% of patients are refractory to immunosuppressive therapy and remain pancytopenic after therapy. Even patients that respond to immunosuppressive therapies with an improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia .

Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant number of patients have persistent cytopenias. Currently, the treatment of these patients is regular transfusion, which are expensive, inconvenient, and associated with serious side effects related to iron overload and transfusion.

Thrombopoietin is a glycoprotein class 1 hematopoietic cytokine, produced primarily in the liver. It is a critical regulator of hematopoiesis. It acts through the thrombopoietin receptor which is expressed on hematopoietic stem and progenitor cells. Action results in a number of signal transduction events that prevent apoptosis, improve cell viability, promote growth, and possibly increase differentiation.

Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site of thrombopoietin therefore it does not compete for binding with the native molecule. It promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote other hematopoietic stem cell as well as in thrombopoiesis .Eltrombopag became the first oral platelet growth factor to receive Food and Drug Administration approval in 2008. This initial indication was for adult patients with chronic immune thrombocytopenic purpura. In 24 August 2015, this indication was extended to children age 1 to 17 with the same condition. In addition, it has been recently shown to be efficacious in the setting of aplastic anemia with trilineage responses in some patients and many achieving transfusion independence. It has license by the European Medicines Agency for this indication in August 2015. In 2017, the National Institutes of Health made Eltrombopag a standard of care in Aplastic anemia

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 5, 2020
• Est. primary completion date: December 29, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

Inclusion Criteria:

Current diagnosis of sever Aplastic anemia

• Diagnosis of sever Aplastic anemia is established if Bone marrow cellularity <25% or and at least two of the following criteria are met:- (i) absolute neutrophil count less than 0.5 × 109/L, (ii) platelet count less than 20 × 109/L, and (iii) reticulocyte count less than 20 × 109/L

• No, evidence of viral or drug suppression of the marrow, dysplasia, or underproduction anemias secondary to B12, folate, iron or other reversible causes.

• Age equal to 1 years old to 18 years old

• Written informed consent signed by a parent or legal guardian prior to initiation of any study specific procedure.

• Hematopoietic stem cell transplantation is not available or suitable as a treatment option or has been refused by the patient.

• Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag

Exclusion Criteria:

Prior and/or active medical history of:-

• Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry). Other known underlying congenital/inherited marrow failure syndromes.

• Symptomatic Paroxysmal Nocturnal Hemoglobinuria

• Other known or suspected underlying primary immunodeficiency

• Any malignancy

• Active infection not responding to appropriate therapy

• Any out of range lab values Creatinine >2.5 mg/dL× the upper limit of normal, Total bilirubin >1.5 × the upper limit of normal mg/dL ,Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of normal

• 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.

Related Conditions & MeSH terms

• Anemia, Aplastic
• Eltrombopag

Intervention

Drug:
• Eltrombopag
An oral thrombopoietin receptor agonist

Locations

Country	Name	City	State
Egypt	Facility of medicine	Assiut

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

Country where clinical trial is conducted

Egypt, 

References & Publications (24)

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Ballmaier M, Germeshausen M, Krukemeier S, Welte K. Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia. Ann N Y Acad Sci. 2003 May;996:17-25. — View Citation

Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. — View Citation

de Laval B, Pawlikowska P, Petit-Cocault L, Bilhou-Nabera C, Aubin-Houzelstein G, Souyri M, Pouzoulet F, Gaudry M, Porteu F. Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage. Cell Stem Cell. 2013 Jan 3;12(1):37-48. doi: 10.1016/j.stem.2012.10.012. Epub 2012 Dec 13. — View Citation

Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, Parikh AR, Broder K, Calvo KR, Wu CO, Young NS, Dunbar CE. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014 Mar 20;123(12):1818-25. doi: 10.1182/blood-2013-10-534743. Epub 2013 Dec 17. — View Citation

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Guinan EC. Acquired aplastic anemia in childhood. Hematol Oncol Clin North Am. 2009 Apr;23(2):171-91. doi: 10.1016/j.hoc.2009.01.011. Review. — View Citation

Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP, Hale GA, Ilhan O, Passweg JR, Ringdén O, Sabloff M, Schrezenmeier H, Socié G, Marsh JC. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010 Dec;95(12):2119-25. doi: 10.3324/haematol.2010.026682. Epub 2010 Sep 17. — View Citation

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Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, Parikh AR, Soto S, Biancotto A, Feng X, Lozier J, Wu CO, Young NS, Dunbar CE. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5;367(1):11-9. doi: 10.1056/NEJMoa1200931. Erratum in: N Engl J Med. 2012 Jul 19;367(3):284. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	changes in Platelet count (at Baseline, 26 Weeks and up to 52 week)	increase of platelet count from baseline by 20,000/microliter or more (in the absence of platelet transfusion), or independence from platelet transfusions for a minimum of 8 weeks in patients who were previously transfusion-dependent.	52 week
Primary	Changes in hemoglobin count (at Baseline, 26 Weeks and up to 52 week)	measuring the following: Increase from baseline by 1.5 gram g/dL or more when the baseline hemoglobin level is <8.5 g/dL and no red blood cell (RBC) transfusion at baseline. A decrease of at least four units in RBC transfusions in the post-treatment 8-week period compared to the pre-treatment 8-week period..	52 week
Primary	changes in absolute Neutrophil count (at Baseline, 26 Weeks and up to 52 week)	measuring the increase in the absolute neutrophil count of more than 500 per cubic millimeter	52 week
Primary	complete response (CR) - 12 month	CR defined as all three parameters meet the following criteria : Hb =100 g/l, platelet count =100 × 109/L, and ANC =1 × 109/L. Additionally, patients had to be transfusion and growth factor independent	52 weeks
Primary	Partial response (PR) - 12 month	PR was defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of sever aplastic anemia (SAA): Absolute neutrophil count (ANC) >500/µL Platelet count >20 000/µL Reticulocyte count >20 000/µL	52 weeks
Secondary	The hematological responses	Duration of hematologic response Time from the date of the start of response to the date of relapse defined as again meeting criteria for severe or moderate aplastic anemia Duration of platelet and blood transfusion independence Transfusion independency is defined when blood and platelet transfusions are not required in a consecutive 8-week period. Transfusion dependency will be defined as at least 2 units of red blood cells or five units of random platelets or equivalent apheresis per month for a period of 8 weeks. The duration of platelet and blood transfusion independence will be evaluated separately.	up to to 52 week
Secondary	The toxicity	Number of participants with adverse events Measure toxicity, using CTCAE associated with assessment of eltrombopag use, dose, and tolerability in patients with sever to very severe aplastic anemia	Up to 30 days after last dose of study treatment
Secondary	complete response (CR)- 6 month	CR defined as all three parameters meet the following criteria : Hb =100 g/l, platelet count =100 × 109/L, and ANC =1 × 109/L. Additionally, patients had to be transfusion and growth factor independent	26 week
Secondary	Partial response (PR) - 6 month	PR was defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA.; Absolute neutrophil count (ANC) >500/µL Platelet count >20 000/µL Reticulocyte count >20 000/µL	26 week
Secondary	Overall hematologic response (CR + PR) rate - 6 month	Overall hematologic response = patients with complete response + patients with partial response .; Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA; ANC >500/µL Platelet count >20 000/µL Reticulocyte count >20 000/µL; Complete response is defined as all three parameters meet the following criteria: ANC > 1 000/µL Platelet count >100 000/µL Hemoglobin >10 g/L	26 week
Secondary	Overall hematologic response (CR + PR) rate - 12 month	Overall hematologic response = patients with complete response + patients with partial response.; Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA; ANC >500/µL Platelet count >20 000/µL Reticulocyte count >20 000/µL; Complete response is defined as all three parameters meet the following criteria: ANC > 1 000/µL Platelet count >100 000/µL Hemoglobin >10 g/L	52 week