- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02877212
Association of FcγRIIIA Polymorphism and THPO Expression With Response to Eltrombopag in Refractory ITP Patients
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
Study Overview
Status
Conditions
Intervention / Treatment
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 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:
- 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.
- 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.
- Fc gamma RIIIA V158F polymorphism will be assessed by means of an allele-specific PCR and/nested PCR following sequence verification
- In order to validate the genotypes of study participants; direct sequencing of the SNPs will be done through automated capillary sequencing method.
- 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.
- 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).
- 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).
- 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) .
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Parvez Ahmed, FCPS, MCPS
- Phone Number: 201 +92-51-9270076
- Email: parvez101@yahoo.com
Study Contact Backup
- Name: Andleeb Hanif, M.Phil
- Phone Number: 232 +92-51-9270076
- Email: andleebhanif123@gmail.com
Study Locations
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Punjab
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Rawalpindi, Punjab, Pakistan, 46000
- Recruiting
- Armed Forces Bone Marrow Transplant Centre
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Contact:
- Andleeb Hanif, M.Phil
- Phone Number: 232 +92-51-9270076
- Email: andleebhanif123@gmail.com
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Contact:
- Parvez Ahmed, FCPS, MCPS
- Phone Number: 201 +92-51-9270076
- Email: pahmed101@yahoo.com
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Principal Investigator:
- Parvez Ahmed, FCPS, MCPS
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Sub-Investigator:
- Andleeb Hanif, M.Phil
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Sub-Investigator:
- Tariq M Satti, FCPS
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Sub-Investigator:
- Qamar Un Nisa Ch, FCPS
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Sub-Investigator:
- Kamran Mehmood, FCPS
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Steroid refractory ITP defined according to the recent consensual criteria (Rodeghiero F et al. Blood 2009),
- 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:
- Secondary ITP
- Other hematological and malignant disorders
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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
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Eltrombopag will be given to steroid refractory ITP patients and ITP patients treated with standard Immunosuppressive therapy (IST) will be taken as control.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The overall response rate 4-6 months after treatment defined by a platelet count > 30 x 109/L with at least a two-fold increase from the initial (pre-treatment) count
Time Frame: 6 months after inclusion
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6 months after inclusion
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Fc Receptor polymorphism and THPO expression in responders and non-responders
Time Frame: 6-12 months after inclusion
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The inclusion of 75 patients (25 ITP patients treated with Eltrombopag and 50 subjects with ITP treated with other standard IST) would be considered as sufficient to show an association of the FcgammaRIIIA V158F genotypes distribution and THPO expression with the response for the patients treated with Eltrombopag and other IST at different time points; (M0, M3 and M6 )** **M0=pretreatment sample at 0 month; M3=sample after 3 months of treatment; M6= sample after 6 months of treatment.
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6-12 months after inclusion
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The Thrombopoietin and cytokine expression among the responders and non responders
Time Frame: 6 months
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The Thrombopoietin and cytokine expression among the responders and non responders will be taken as secondary outcome to evaluate the influence of Fc gamma RIIIA mutated genotypes to evaluate the correlation between steroid refractory and control groups.
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6 months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Parvez Ahmed, FCPS, MCPS, Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan
- Study Director: Andleeb Hanif, M.Phil, andleebhanif123@gmail.com
Publications and helpful links
General Publications
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Autoimmune Diseases
- Hematologic Diseases
- Hemorrhage
- Hemorrhagic Disorders
- Blood Coagulation Disorders
- Skin Manifestations
- Thrombocytopenia
- Blood Platelet Disorders
- Thrombotic Microangiopathies
- Purpura
- Purpura, Thrombocytopenic
- Purpura, Thrombocytopenic, Idiopathic
Other Study ID Numbers
- AFBMTC_ITP_2016
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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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