<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03243656</url>
  </required_header>
  <id_info>
    <org_study_id>MAAhmed</org_study_id>
    <nct_id>NCT03243656</nct_id>
  </id_info>
  <brief_title>Eltrombopag &amp; Cyclosporine in Children With Sever Aplastic Anemia</brief_title>
  <acronym>Eltroplastic</acronym>
  <official_title>Randomized Clinical Trial of the Use of &amp; Cyclosporine in Children With Sever Idiopathic Aplastic Anemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone&#xD;
      marrow.but,It is very serious disease causing morbidity and mortality.&#xD;
&#xD;
      Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and&#xD;
      immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations&#xD;
      due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant&#xD;
      number of patients have persistent cytopenias. Currently, the treatment of these patients is&#xD;
      regular transfusion, which are expensive, inconvenient, and associated with serious side&#xD;
      effects related to iron overload and transfusion.&#xD;
&#xD;
      Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and&#xD;
      juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site&#xD;
      of thrombopoietin therefore it does not compete for binding with the native molecule. It&#xD;
      promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote&#xD;
      other hematopoietic stem cell as well as in thrombopoiesis .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone&#xD;
      marrow.This causes a deficiency of all three blood cell types (pancytopenia): red blood cells&#xD;
      (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia) . The clinical&#xD;
      consequences are anemia, usually with a requirement for frequent red blood cell transfusions,&#xD;
      life-threatening bleeding from thrombocytopenia, and infection because of neutropenia.&#xD;
      Bacterial and fungal infections are most common and are a significant cause of morbidity and&#xD;
      mortality.&#xD;
&#xD;
      The incidence of acquired Aplastic anemia in Europe and North America is around two per&#xD;
      million children per year . The incidence is 2-3 times higher in East Asia. There is no&#xD;
      significant difference in incidence between males and females .&#xD;
&#xD;
      The pathogenesis of Aplastic anemia is complex and involves an abnormal hematopoietic&#xD;
      microenvironment, hematopoietic stem cell/progenitor cell deficiencies and immunity&#xD;
      disorders. The etiological basis for marrow failure includes primary defects in or damage to&#xD;
      the stem cell or the marrow microenvironment. The distinction between acquired and inherited&#xD;
      disease may present a clinical challenge, Congenital or inherited causes of Aplastic anemia&#xD;
      are responsible for at least 25% of children with this condition and for perhaps up to 10% of&#xD;
      adults. Acquired causes of Aplastic anemia form (80%) of cases, include Idiopathic (&gt; 80 %),&#xD;
      Post-infectious 15% (particularly after hepatitis 9%, Epstein-Barr virus , human immune&#xD;
      deficiency virus, parvovirus, and mycobacteria, Drug-induced and toxins (4%).&#xD;
&#xD;
      Definitive and potentially curative therapy with haematopoietic stem cell transplantation&#xD;
      However, only a minority (30 %) of patients have a suitable donor. Immunosuppressive therapy&#xD;
      with horse or rabbit antithymocyte globulin plus cyclosporine is the most commonly used&#xD;
      alternative treatment in about two thirds of cases. Response is associated with a favorable&#xD;
      long-term outlook. 30 -40% of patients are refractory to immunosuppressive therapy and remain&#xD;
      pancytopenic after therapy. Even patients that respond to immunosuppressive therapies with an&#xD;
      improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia&#xD;
      .&#xD;
&#xD;
      Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and&#xD;
      immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations&#xD;
      due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant&#xD;
      number of patients have persistent cytopenias. Currently, the treatment of these patients is&#xD;
      regular transfusion, which are expensive, inconvenient, and associated with serious side&#xD;
      effects related to iron overload and transfusion.&#xD;
&#xD;
      Thrombopoietin is a glycoprotein class 1 hematopoietic cytokine, produced primarily in the&#xD;
      liver. It is a critical regulator of hematopoiesis. It acts through the thrombopoietin&#xD;
      receptor which is expressed on hematopoietic stem and progenitor cells. Action results in a&#xD;
      number of signal transduction events that prevent apoptosis, improve cell viability, promote&#xD;
      growth, and possibly increase differentiation.&#xD;
&#xD;
      Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and&#xD;
      juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site&#xD;
      of thrombopoietin therefore it does not compete for binding with the native molecule. It&#xD;
      promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote&#xD;
      other hematopoietic stem cell as well as in thrombopoiesis .Eltrombopag became the first oral&#xD;
      platelet growth factor to receive Food and Drug Administration approval in 2008. This initial&#xD;
      indication was for adult patients with chronic immune thrombocytopenic purpura. In 24 August&#xD;
      2015, this indication was extended to children age 1 to 17 with the same condition. In&#xD;
      addition, it has been recently shown to be efficacious in the setting of aplastic anemia with&#xD;
      trilineage responses in some patients and many achieving transfusion independence. It has&#xD;
      license by the European Medicines Agency for this indication in August 2015. In 2017, the&#xD;
      National Institutes of Health made Eltrombopag a standard of care in Aplastic anemia&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 20, 2017</start_date>
  <completion_date type="Actual">January 5, 2020</completion_date>
  <primary_completion_date type="Actual">December 29, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>changes in Platelet count (at Baseline, 26 Weeks and up to 52 week)</measure>
    <time_frame>52 week</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in hemoglobin count (at Baseline, 26 Weeks and up to 52 week)</measure>
    <time_frame>52 week</time_frame>
    <description>measuring the following: Increase from baseline by 1.5 gram g/dL or more when the baseline hemoglobin level is &lt;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..</description>
  </primary_outcome>
  <primary_outcome>
    <measure>changes in absolute Neutrophil count (at Baseline, 26 Weeks and up to 52 week)</measure>
    <time_frame>52 week</time_frame>
    <description>measuring the increase in the absolute neutrophil count of more than 500 per cubic millimeter</description>
  </primary_outcome>
  <primary_outcome>
    <measure>complete response (CR) - 12 month</measure>
    <time_frame>52 weeks</time_frame>
    <description>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</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Partial response (PR) - 12 month</measure>
    <time_frame>52 weeks</time_frame>
    <description>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) &gt;500/μL Platelet count &gt;20 000/μL Reticulocyte count &gt;20 000/μL</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The hematological responses</measure>
    <time_frame>up to to 52 week</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The toxicity</measure>
    <time_frame>Up to 30 days after last dose of study treatment</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>complete response (CR)- 6 month</measure>
    <time_frame>26 week</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Partial response (PR) - 6 month</measure>
    <time_frame>26 week</time_frame>
    <description>PR was defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA.&#xD;
Absolute neutrophil count (ANC) &gt;500/μL Platelet count &gt;20 000/μL Reticulocyte count &gt;20 000/μL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall hematologic response (CR + PR) rate - 6 month</measure>
    <time_frame>26 week</time_frame>
    <description>Overall hematologic response = patients with complete response + patients with partial response .&#xD;
Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA&#xD;
ANC &gt;500/μL Platelet count &gt;20 000/μL Reticulocyte count &gt;20 000/μL&#xD;
Complete response is defined as all three parameters meet the following criteria:&#xD;
ANC &gt; 1 000/μL Platelet count &gt;100 000/μL Hemoglobin &gt;10 g/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall hematologic response (CR + PR) rate - 12 month</measure>
    <time_frame>52 week</time_frame>
    <description>Overall hematologic response = patients with complete response + patients with partial response.&#xD;
Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA&#xD;
ANC &gt;500/μL Platelet count &gt;20 000/μL Reticulocyte count &gt;20 000/μL&#xD;
Complete response is defined as all three parameters meet the following criteria:&#xD;
ANC &gt; 1 000/μL Platelet count &gt;100 000/μL Hemoglobin &gt;10 g/L</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Eltrombopag</condition>
  <arm_group>
    <arm_group_label>historical group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Immunosuppressive therapy (cyclosporine alone ),</description>
  </arm_group>
  <arm_group>
    <arm_group_label>case arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>cyclosporine plus an oral dose of Eltrombopag</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eltrombopag</intervention_name>
    <description>An oral thrombopoietin receptor agonist</description>
    <arm_group_label>case arm</arm_group_label>
    <other_name>Revolade</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Current diagnosis of sever Aplastic anemia&#xD;
&#xD;
          -  Diagnosis of sever Aplastic anemia is established if Bone marrow cellularity &lt;25% or&#xD;
             and at least two of the following criteria are met:- (i) absolute neutrophil count&#xD;
             less than 0.5 × 109/L, (ii) platelet count less than 20 × 109/L, and (iii)&#xD;
             reticulocyte count less than 20 × 109/L&#xD;
&#xD;
          -  No, evidence of viral or drug suppression of the marrow, dysplasia, or underproduction&#xD;
             anemias secondary to B12, folate, iron or other reversible causes.&#xD;
&#xD;
          -  Age equal to 1 years old to 18 years old&#xD;
&#xD;
          -  Written informed consent signed by a parent or legal guardian prior to initiation of&#xD;
             any study specific procedure.&#xD;
&#xD;
          -  Hematopoietic stem cell transplantation is not available or suitable as a treatment&#xD;
             option or has been refused by the patient.&#xD;
&#xD;
          -  Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of&#xD;
             eltrombopag&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Prior and/or active medical history of:-&#xD;
&#xD;
          -  Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry).&#xD;
             Other known underlying congenital/inherited marrow failure syndromes.&#xD;
&#xD;
          -  Symptomatic Paroxysmal Nocturnal Hemoglobinuria&#xD;
&#xD;
          -  Other known or suspected underlying primary immunodeficiency&#xD;
&#xD;
          -  Any malignancy&#xD;
&#xD;
          -  Active infection not responding to appropriate therapy&#xD;
&#xD;
          -  Any out of range lab values Creatinine &gt;2.5 mg/dL× the upper limit of normal, Total&#xD;
             bilirubin &gt;1.5 × the upper limit of normal mg/dL ,Aspartate aminotransferase (AST) or&#xD;
             alanine aminotransferase (ALT) &gt;2.5 × the upper limit of normal&#xD;
&#xD;
          -  Hypersensitivity to eltrombopag or its components&#xD;
&#xD;
          -  Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,&#xD;
             infectious, or metabolic disease of such severity that it would preclude the patient's&#xD;
             ability to tolerate protocol therapy, or that death within 7-10 days is likely.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Facility of medicine</name>
      <address>
        <city>Assiut</city>
        <zip>71511</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>19327578</PMID>
  </reference>
  <reference>
    <citation>Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S119-25. doi: 10.1016/j.bbmt.2009.09.013. Epub 2009 Sep 24.</citation>
    <PMID>19782144</PMID>
  </reference>
  <reference>
    <citation>Issaragrisil S, Kaufman DW, Anderson T, Chansung K, Leaverton PE, Shapiro S, Young NS. The epidemiology of aplastic anemia in Thailand. Blood. 2006 Feb 15;107(4):1299-307. doi: 10.1182/blood-2005-01-0161. Epub 2005 Oct 27.</citation>
    <PMID>16254144</PMID>
  </reference>
  <reference>
    <citation>Marsh JC, Mufti GJ. Eltrombopag: a stem cell cookie? Blood. 2014 Mar 20;123(12):1774-5. doi: 10.1182/blood-2014-02-553404. No abstract available.</citation>
    <PMID>24652959</PMID>
  </reference>
  <reference>
    <citation>Garnock-Jones KP, Keam SJ. Eltrombopag. Drugs. 2009;69(5):567-76. doi: 10.2165/00003495-200969050-00005.</citation>
    <PMID>19368418</PMID>
  </reference>
  <reference>
    <citation>Montane E, Ibanez L, Vidal X, Ballarin E, Puig R, Garcia N, Laporte JR; Catalan Group for Study of Agranulocytosis and Aplastic Anemia. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008 Apr;93(4):518-23. doi: 10.3324/haematol.12020. Epub 2008 Mar 5.</citation>
    <PMID>18322256</PMID>
  </reference>
  <reference>
    <citation>Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, Mansson R, Thoren LA, Ekblom M, Alexander WS, Jacobsen SE. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2007 Dec 13;1(6):671-84. doi: 10.1016/j.stem.2007.10.008. Epub 2007 Nov 20.</citation>
    <PMID>18371408</PMID>
  </reference>
  <reference>
    <citation>Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood. 2008 Feb 1;111(3):981-6. doi: 10.1182/blood-2007-05-088500.</citation>
    <PMID>18223171</PMID>
  </reference>
  <reference>
    <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. doi: 10.1056/NEJMoa073275.</citation>
    <PMID>18046028</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>23246483</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22762314</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>24345753</PMID>
  </reference>
  <reference>
    <citation>Alter BP. Aplastic Anemia, Pediatric Aspects. Oncologist. 1996;1(6):361-366.</citation>
    <PMID>10388017</PMID>
  </reference>
  <reference>
    <citation>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. doi: 10.1111/j.1749-6632.2003.tb03228.x.</citation>
    <PMID>12799278</PMID>
  </reference>
  <reference>
    <citation>Dezern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev Hematol. 2011 Apr;4(2):221-30. doi: 10.1586/ehm.11.11.</citation>
    <PMID>21495931</PMID>
  </reference>
  <reference>
    <citation>Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP, Hale GA, Ilhan O, Passweg JR, Ringden O, Sabloff M, Schrezenmeier H, Socie 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.</citation>
    <PMID>20851870</PMID>
  </reference>
  <reference>
    <citation>Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, Keidan J, Laurie A, Martin A, Mercieca J, Killick SB, Stewart R, Yin JA; British Committee for Standards in Haematology. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009 Oct;147(1):43-70. doi: 10.1111/j.1365-2141.2009.07842.x. Epub 2009 Aug 10. No abstract available.</citation>
    <PMID>19673883</PMID>
  </reference>
  <reference>
    <citation>Rauff B, Idrees M, Shah SA, Butt S, Butt AM, Ali L, Hussain A, Irshad-Ur-Rehman, Ali M. Hepatitis associated aplastic anemia: a review. Virol J. 2011 Feb 28;8:87. doi: 10.1186/1743-422X-8-87.</citation>
    <PMID>21352606</PMID>
  </reference>
  <reference>
    <citation>Young NS. Pathophysiologic mechanisms in acquired aplastic anemia. Hematology Am Soc Hematol Educ Program. 2006:72-7. doi: 10.1182/asheducation-2006.1.72.</citation>
    <PMID>17124043</PMID>
  </reference>
  <reference>
    <citation>Zhang J, Yang T. [Meta-analysis of association between organophosphorus pesticides and aplastic anemia]. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Sep;36(9):1005-9. Chinese.</citation>
    <PMID>26814872</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, Xian Y, Dai BT, Xu YH, Su YC. [Hematopoiesis support of mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Aug;10(4):455-9. Chinese.</citation>
    <PMID>18706160</PMID>
  </reference>
  <reference>
    <citation>Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012:292-300. doi: 10.1182/asheducation-2012.1.292.</citation>
    <PMID>23233595</PMID>
  </reference>
  <reference>
    <citation>Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430-8. doi: 10.1056/NEJMoa1103975. Erratum In: N Engl J Med. 2018 Jun 13;:null.</citation>
    <PMID>21812672</PMID>
  </reference>
  <reference>
    <citation>Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.</citation>
    <PMID>28423296</PMID>
  </reference>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>January 13, 2022</last_update_submitted>
  <last_update_submitted_qc>January 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Mai Ali Abdelfatah Ahmed</investigator_full_name>
    <investigator_title>assistant lecturer</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Aplastic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03243656
org study id: MAAhmed
nct id: NCT03243656
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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 .
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: changes in Platelet count (at Baseline, 26 Weeks and up to 52 week)
time frame: 52 week
description: 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.
measure: Changes in hemoglobin count (at Baseline, 26 Weeks and up to 52 week)
time frame: 52 week
description: 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..
measure: changes in absolute Neutrophil count (at Baseline, 26 Weeks and up to 52 week)
time frame: 52 week
description: measuring the increase in the absolute neutrophil count of more than 500 per cubic millimeter
measure: complete response (CR) - 12 month
time frame: 52 weeks
description: 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
measure: Partial response (PR) - 12 month
time frame: 52 weeks
description: 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
measure: The hematological responses
time frame: up to to 52 week
description: 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.
measure: The toxicity
time frame: Up to 30 days after last dose of study treatment
description: 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
measure: complete response (CR)- 6 month
time frame: 26 week
description: 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
measure: Partial response (PR) - 6 month
time frame: 26 week
description: 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
measure: Overall hematologic response (CR + PR) rate - 6 month
time frame: 26 week
description: 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
measure: Overall hematologic response (CR + PR) rate - 12 month
time frame: 52 week
description: 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
arm group label: historical group
arm group type: No Intervention
description: Immunosuppressive therapy (cyclosporine alone ),
arm group label: case arm
arm group type: Active Comparator
description: cyclosporine plus an oral dose of Eltrombopag
intervention type: Drug
intervention name: Eltrombopag
description: An oral thrombopoietin receptor agonist
arm group label: case arm
other name: Revolade
criteria: 
gender: All
minimum age: 1 Year
maximum age: 18 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Egypt
citation: 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.
PMID: 19327578
citation: Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S119-25. doi: 10.1016/j.bbmt.2009.09.013. Epub 2009 Sep 24.
PMID: 19782144
citation: Issaragrisil S, Kaufman DW, Anderson T, Chansung K, Leaverton PE, Shapiro S, Young NS. The epidemiology of aplastic anemia in Thailand. Blood. 2006 Feb 15;107(4):1299-307. doi: 10.1182/blood-2005-01-0161. Epub 2005 Oct 27.
PMID: 16254144
citation: Marsh JC, Mufti GJ. Eltrombopag: a stem cell cookie? Blood. 2014 Mar 20;123(12):1774-5. doi: 10.1182/blood-2014-02-553404. No abstract available.
PMID: 24652959
citation: Garnock-Jones KP, Keam SJ. Eltrombopag. Drugs. 2009;69(5):567-76. doi: 10.2165/00003495-200969050-00005.
PMID: 19368418
citation: Montane E, Ibanez L, Vidal X, Ballarin E, Puig R, Garcia N, Laporte JR; Catalan Group for Study of Agranulocytosis and Aplastic Anemia. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008 Apr;93(4):518-23. doi: 10.3324/haematol.12020. Epub 2008 Mar 5.
PMID: 18322256
citation: Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, Mansson R, Thoren LA, Ekblom M, Alexander WS, Jacobsen SE. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2007 Dec 13;1(6):671-84. doi: 10.1016/j.stem.2007.10.008. Epub 2007 Nov 20.
PMID: 18371408
citation: Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood. 2008 Feb 1;111(3):981-6. doi: 10.1182/blood-2007-05-088500.
PMID: 18223171
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. doi: 10.1056/NEJMoa073275.
PMID: 18046028
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.
PMID: 23246483
citation: 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.
PMID: 22762314
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.
PMID: 24345753
citation: Alter BP. Aplastic Anemia, Pediatric Aspects. Oncologist. 1996;1(6):361-366.
PMID: 10388017
citation: 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. doi: 10.1111/j.1749-6632.2003.tb03228.x.
PMID: 12799278
citation: Dezern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev Hematol. 2011 Apr;4(2):221-30. doi: 10.1586/ehm.11.11.
PMID: 21495931
citation: Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP, Hale GA, Ilhan O, Passweg JR, Ringden O, Sabloff M, Schrezenmeier H, Socie 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.
PMID: 20851870
citation: Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, Keidan J, Laurie A, Martin A, Mercieca J, Killick SB, Stewart R, Yin JA; British Committee for Standards in Haematology. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009 Oct;147(1):43-70. doi: 10.1111/j.1365-2141.2009.07842.x. Epub 2009 Aug 10. No abstract available.
PMID: 19673883
citation: Rauff B, Idrees M, Shah SA, Butt S, Butt AM, Ali L, Hussain A, Irshad-Ur-Rehman, Ali M. Hepatitis associated aplastic anemia: a review. Virol J. 2011 Feb 28;8:87. doi: 10.1186/1743-422X-8-87.
PMID: 21352606
citation: Young NS. Pathophysiologic mechanisms in acquired aplastic anemia. Hematology Am Soc Hematol Educ Program. 2006:72-7. doi: 10.1182/asheducation-2006.1.72.
PMID: 17124043
citation: Zhang J, Yang T. [Meta-analysis of association between organophosphorus pesticides and aplastic anemia]. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Sep;36(9):1005-9. Chinese.
PMID: 26814872
citation: Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, Xian Y, Dai BT, Xu YH, Su YC. [Hematopoiesis support of mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Aug;10(4):455-9. Chinese.
PMID: 18706160
citation: Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012:292-300. doi: 10.1182/asheducation-2012.1.292.
PMID: 23233595
citation: Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430-8. doi: 10.1056/NEJMoa1103975. Erratum In: N Engl J Med. 2018 Jun 13;:null.
PMID: 21812672
citation: Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.
PMID: 28423296
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Mai Ali Abdelfatah Ahmed
investigator title: assistant lecturer
mesh term: Anemia, Aplastic
sharing ipd: No