Eltrombopag & Cyclosporine in Children With Sever Aplastic Anemia

NCT03243656 | Completed Phase 4

• 1 other identifier: MAAhmed
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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 .

Conditions

Eltrombopag

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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 Outcomes (6)

• The hematological responses

  up to to 52 week

• The toxicity

  Up to 30 days after last dose of study treatment

• complete response (CR)- 6 month

  26 week

• Partial response (PR) - 6 month

  26 week

• Overall hematologic response (CR + PR) rate - 6 month

  26 week

Study Arms (2)

historical group

NO INTERVENTION

Immunosuppressive therapy (cyclosporine alone ),

case arm

ACTIVE COMPARATOR

cyclosporine plus an oral dose of Eltrombopag

Drug: Eltrombopag

Interventions

Eltrombopag DRUG

An oral thrombopoietin receptor agonist

Also known as: Revolade

case arm

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assiut University: lead

Study Sites (1)

Facility of medicine

Asyut, 71511, Egypt

Location

Related Publications (24)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Garnock-Jones KP, Keam SJ. Eltrombopag. Drugs. 2009;69(5):567-76. doi: 10.2165/00003495-200969050-00005.

  PMID: 19368418 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood. 2008 Feb 1;111(3):981-6. doi: 10.1182/blood-2007-05-088500.

  PMID: 18223171 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

  PMID: 22762314 BACKGROUND

• 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 BACKGROUND

• Alter BP. Aplastic Anemia, Pediatric Aspects. Oncologist. 1996;1(6):361-366.

  PMID: 10388017 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

  PMID: 21812672 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Interventions

eltrombopag

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: assistant lecturer

Study Record Dates

• First Submitted: August 2, 2017
• First Posted: August 9, 2017
• Study Start: December 20, 2017
• Primary Completion: December 29, 2019
• Study Completion: January 5, 2020
• Last Updated: January 18, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)