Eltrombopag & Cyclosporine in Children With Sever Aplastic Anemia (Eltroplastic)

January 13, 2022 updated by: Mai Ali Abdelfatah Ahmed, Assiut University

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

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 .

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Assiut, Egypt, 71511
        • Facility of medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: historical group
Immunosuppressive therapy (cyclosporine alone ),
Active Comparator: case arm
cyclosporine plus an oral dose of Eltrombopag
Drug: Eltrombopag
An oral thrombopoietin receptor agonist
Other Names:
  • Revolade

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
changes in Platelet count (at Baseline, 26 Weeks and up to 52 week)
Time Frame: 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
Changes in hemoglobin count (at Baseline, 26 Weeks and up to 52 week)
Time Frame: 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
changes in absolute Neutrophil count (at Baseline, 26 Weeks and up to 52 week)
Time Frame: 52 week
measuring the increase in the absolute neutrophil count of more than 500 per cubic millimeter
52 week
complete response (CR) - 12 month
Time Frame: 52 weeks
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
Partial response (PR) - 12 month
Time Frame: 52 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
The hematological responses
Time Frame: up to to 52 week
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
The toxicity
Time Frame: Up to 30 days after last dose of study treatment
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
complete response (CR)- 6 month
Time Frame: 26 week
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
Partial response (PR) - 6 month
Time Frame: 26 week

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
Overall hematologic response (CR + PR) rate - 6 month
Time Frame: 26 week

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
Overall hematologic response (CR + PR) rate - 12 month
Time Frame: 52 week

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 20, 2017

Primary Completion (Actual)

December 29, 2019

Study Completion (Actual)

January 5, 2020

Study Registration Dates

First Submitted

August 2, 2017

First Submitted That Met QC Criteria

August 4, 2017

First Posted (Actual)

August 9, 2017

Study Record Updates

Last Update Posted (Actual)

January 18, 2022

Last Update Submitted That Met QC Criteria

January 13, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MAAhmed

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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