Ignite Creation Date:
2024-05-06 @ 9:00 AM
Last Modification Date:
2024-10-26 @ 12:08 PM
Study NCT ID:
NCT02877212
Status:
UNKNOWN
Last Update Posted:
2016-08-24
First Post:
2016-08-15
Brief Title:
Association of FcγRIIIA Polymorphism and THPO Expression With Response to Eltrombopag in Refractory ITP Patients
Sponsor:
National Institute of Blood and Marrow Transplant NIBMT Pakistan
Organization:
National Institute of Blood and Marrow Transplant NIBMT Pakistan
Study Overview
Official Title:
Association of FC Gamma RIIIA Polymorphism and Thrombopoietin THPO Expression With Response to TPO Agonists in Refractory ITP and the Impact of Therapy on B and T Cells Subsets in the Patients With Mutated Genotypes
Status:
UNKNOWN
Status Verified Date:
2016-08
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Idiopathic thrombocytopenic purpura ITP is an autoimmune disease characterized by antibody-mediated platelet destruction The complex pathogenesis of ITP with multiple challenges to immune system in terms of genetic predisposition infection responsiveness to immunosuppressive therapy IST and inhibition of platelet production has proven the diversity of constraints in diagnosing and treating ITP Thrombopoietin receptor agonist Eltrombopag 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 This clinical trial aims to investigate the association of Fc gammaRIIIA gene V158F genetic predisposition with treatment outcome of Immune Thrombocytopenia ITP in refractory ITP patients and especially with Eltrombopag
Detailed Description:
Immune thrombocytopenic purpura ITP is a autoimmune disorder in which a decreased number of circulating platelets thrombocytopenia manifests as a bleeding tendency easy bruising purpura or extravasation of blood from capillaries into skin and mucous membranes petechiae
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 productionIt 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 109L 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 andnested 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 RD 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 230
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 productionIt 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 109L 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 andnested 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 RD 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 230
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None