Association of FcγRIIIA Polymorphism and THPO Expression With Response to Eltrombopag in Refractory ITP Patients
NCT ID: NCT02877212
Last Updated: 2016-08-24
Study Results
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Basic Information
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UNKNOWN
PHASE3
75 participants
INTERVENTIONAL
2016-07-31
2017-09-30
Brief Summary
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Detailed Description
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In persons with ITP, platelets are coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased platelet count.
In immune thrombocytopenic purpura (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins (GPs), binds to circulating platelet membranes to induce clinically significant platelet dysfunction by directly blocking access of agonists to platelet Gp receptors.
Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets.
Polymorphisms in FcγRIIIA have been implicated in responsiveness to splenectomy, corticosteroids and rituximab. Current trial is designed to investigate the impact of genetic predisposition of FcγRIIIA polymorphisms in refractory ITP patients treated with Eltrombopag along with cytokine profile expression in responders and non responders.
Eltrombopag is a small molecule thrombopoietin receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the thrombopoietin receptor (also known as cMpl) leading to increased platelet production.It is specifically indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Eltrombopag is supplied as a tablet designed for oral administration. In Pakistan, where patients; who are of East Asian ancestry or who have moderate to severe hepatic impairment, the recommended initial dose of Eltrombopag is 25 mg once daily. Eltrombopag should be adjusted to achieve and maintain a platelet count \>50 x 109/L as necessary to reduce the risk for bleeding. The dosing of Eltrombopag should not exceed 75 mg daily.
Methodology:
1. Blood samples (serum, plasma, DNA\*) will be collected from 50 controls (treated with standard immunosuppressive therapy (IST) as first and second line treatment) and 25 patients (steroids refractory) at the time of enrollment to the trial (pre-treatment; 0) and then sequentially at 3 and 6 months after treatment.
2. When a marrow analysis is indicated, some marrow specimens will also be collected and studied and if a patient to undergoes splenectomy as part of treatment, spleen specimens will also be collected and cryopreserved.
3. Fc gamma RIIIA V158F polymorphism will be assessed by means of an allele-specific PCR and/nested PCR following sequence verification
4. In order to validate the genotypes of study participants; direct sequencing of the SNPs will be done through automated capillary sequencing method.
5. Thrombopoietin (THPO) expression will be quantified before treatment and at 0, 3 and 6 months after treatment by real time PCR using house keeping gene (Beta Actin) as positive control in the refractory and control subjects.
6. The sequential analysis of T cells and anti-platelets (anti-GpIIbIIIa) antibodies producing B cells will be performed before and after treatment by means of flow cytometry in order to characterize T cells (TH1, TH2, TH17, TFH, Tregs subsets) and B cells (CD19+ representing B cell regulators).
7. Immune cells expressing cytokines in subjects with wild type and mutated genotypes will be measured to investigate its correlation with platelet recovery in responders and non responders by using Human Thrombopoietin Luminex performance Assay (R\&D system Inc.; Bead-based multiplex assay for the Luminex® platform).
8. To find the association of the Fc V158F genotypic distribution with THPO and cytokine expression in THPO agonists responders and nonresponders ; statistical analysis will be performed by using statistical program SPSS (Version 23.0) .
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Study subjects
Steroid refractory ITP patients will be given Eltrombopag to investigate the association of treatment outcome with Fc Receptor polymorphism and THPO expression in responders and non responders following comparison correlation with ITP patients treated with standard IST as control group
Eltrombopag
Eltrombopag will be given to steroid refractory ITP patients and ITP patients treated with standard Immunosuppressive therapy (IST) will be taken as control.
Interventions
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Eltrombopag
Eltrombopag will be given to steroid refractory ITP patients and ITP patients treated with standard Immunosuppressive therapy (IST) will be taken as control.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Informed consent. The control patients will be included as under;
* Age and sex matched controls
* Control ITP group (treated with standard immunosuppressive therapy (IST) as first and second line treatment)
Exclusion Criteria
* Other hematological and malignant disorders
18 Years
65 Years
ALL
No
Sponsors
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Novartis
INDUSTRY
National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
OTHER_GOV
Responsible Party
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Parvez Ahmed
FCPS, MCPS
Principal Investigators
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Parvez Ahmed, FCPS, MCPS
Role: PRINCIPAL_INVESTIGATOR
Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan
Locations
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Armed Forces Bone Marrow Transplant Centre
Rawalpindi, Punjab Province, Pakistan
Countries
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Central Contacts
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Facility Contacts
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References
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Erickson-Miller CL, Delorme E, Tian SS, Hopson CB, Landis AJ, Valoret EI, Sellers TS, Rosen J, Miller SG, Luengo JI, Duffy KJ, Jenkins JM. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009 Feb;27(2):424-30. doi: 10.1634/stemcells.2008-0366.
Nimmerjahn F. Immunomodulation of immunothrombocytopenia. Semin Hematol. 2016 Apr;53 Suppl 1:S10-2. doi: 10.1053/j.seminhematol.2016.04.004. Epub 2016 Apr 6.
Akyol Erikci A, Karagoz B, Bilgi O. Regulatory T Cells in Patients with Idiopathic Thrombocytopenic Purpura. Turk J Haematol. 2016 Jun 5;33(2):153-5. doi: 10.4274/tjh.2015.0335.
Milosevic I, Slade E, Drysdale H; COMPare project team. Eltrombopag for chronic immune thrombocytopenia. Lancet. 2016 Jan 23;387(10016):336. doi: 10.1016/S0140-6736(16)00107-0. No abstract available.
Other Identifiers
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AFBMTC_ITP_2016
Identifier Type: -
Identifier Source: org_study_id
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