The Effect of Eltrombopag on the Expression of Platelet Collagen Receptor GPVI in Pediatric ITP.

October 26, 2021 updated by: Nayera Hazaa Elsherif

Evaluation of the Effect of Eltrombopag on the Expression of Platelet Collagen Receptor Glycoprotein VI (GPVI) in Pediatric Patients With Chronic and Persistent Immune Thrombocytopenia.

Using eltronmobag as an alternative pathway, which depend on stimulation of thrombocyte synthesis, in chronic and persistent immune thrombocytopenia may be more promising treatment than the classic type, not only by increasing platelets count but also through enhancing of the platelets activation and upregulation of GPVI expression on platelet surface.

This study will include 40 pediatric patients with chronic or persistent ITP, recruited from the Hematology clinic of pediatric hospital Ain Shams University, aiming to investigate the efficacy, & the safety and tolerability of eltrombopag therapy for children as well as the ability of eltrombopag to enhance the platelet activation through the up-regulation of glycoprotein VI (GPVI) receptor expression in comparison with other lines of treatment.

Patients will be divided into 2 groups : Group 1 on eltrombopag ; Group 2 : receiving other lines of therapy .

All Patients will be subjected to :

  1. bleeding score assessment ( baseline &every month ) and Health related quality of life based on Kids' ITP Tools (KIT) questionnaires( baseline and week 24 )
  2. Baseline and at week 24 bone marrow examination with reticulin stain
  3. clinical examination every 2 weeks and complete blood counts.
  4. Assessment of soluble form of glycoprotein VI using sandwich enzyme-linked immunosorbent assay (ELISA) as well as assessment of platelet activation by GPVI using flowcytometry (Gardiner, etal.,2010 ) at baseline and at the end of 6 months treatment period

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 100 ×109/l and the absence of any obvious initiating and/ or underlying cause of the thrombocytopenia. (Buchanan, 1989).

Novel thrombopoiesis-stimulating agents have been developed increasing platelet production by overdriving the system and thereby correcting the thrombocytopenia (Cines etal., 2002). Because these peptides bear no structural resemblance to thrombopoietin agonist(TPO) but still bind and activate the TPO receptor, these compounds are called TPO receptor agonists (TRAs). (Meletis etal.,2010).

Newly formed young platelets are larger and express higher levels of glycoprotein Ibα (GPIbα), which decreases as platelets age. For the purpose of quantitative platelet analysis, GPIbα of the GPIb-IX-V complex and GPVI are of particular interest because these receptors are essentially platelet specific, are critical for initiation of thrombus formation at arterial shear rates, and are implicated in wider platelet functions beyond hemostasis and thrombosis, as well as platelet aging and clearance. (Gardiner etal., 2014).

GP VI is thought to be the major signaling receptor involved in platelet activation on exposed collagen. Following GP VI interactions with collagen, platelets initiate strong activation and release the content of alpha and dense granules.( Yun etal.,2016) GPVI expression was upregulated in megakaryocytes after TPO stimulation (Holmes etal., 2002). Eltrombopag could upregulate GPVI expression in ITP patients, thereby enhancing their platelet adhesion capacity leading to reduce bleeding symptoms (Chiou etal.,2015).

The Aim is to :

To investigate the efficacy, & the safety and tolerability of eltrombopag therapy for children with persistent and chronic immune thrombocytopenia as well as the ability of eltrombopag to enhance the platelet activation through the up-regulation of glycoprotein VI (GPVI) receptor expression in comparison with other lines of treatment.

Study methods :

This study will include 40 pediatric patients with chronic or persistent ITP, age ≥ 1 to ≤ 18 years, recruited from the Hematology clinic of pediatric hospital Ain Shams University

  • Baseline bleeding score assessment (ITP-BAT (v1.0) score) and Health related quality of life based on Kids' ITP Tools (KIT) questionnaires will be done.

  • Patients will be divided into 2 groups:

    1. Group 1 (eltrombopag arm n=20 patients): Patients who showed no response (platelet count ≤ 20x109/L) initially for 3 months or relapse after 6 months after at least one prior ITP therapy. patients will receive a total daily dose of eltrombopag of (25-50mg/d). Dose adjustments may be made based on platelets count with an increment of 25mg once per day at 2 weeks intervals (Maximum dose: 75 mg orally once a day). If platelet counts reached more than 200 × 109 per L, the dose will be decreased by 25 mg once per day at 2 weeks intervals. If platelet counts increased to more than 400 × 109 per L, treatment will be interrupted until platelet counts decreases to less than 150 × 109 per L then the dose will be resumed at the next lower dose.

      Patients, who responded poorly to eltrombopag in 6 months or developed adverse effects, will be asked to discontinue the medication. Those who responded will be followed for further 6 month period.

    2. Group 2 (n=20 patients) Patients who are currently receiving other lines of treatment (steroids, IVIG, azathioprine, and rituximab).
  • All patients will be followed clinically every 2 weeks throughout the period of the study for safety and efficacy, and complete blood counts.
  • Baseline and at week 24 bone marrow examination with reticulin stain will be done
  • Baseline and every 3 months liver and kidney function tests. Throughout the study periods, patients with increased serum alanine transaminase (ALT) ≥ 3 times upper limit normal (ULN) with a total bilirubin ≥2 times ULN or those with increased serum ALT ≥ 5 times ULN will be withdrawn, as well as patients with increased serum creatinine above ULN.
  • Adverse events, episodes of bleeding and bleeding score will be collected and evaluated every month throughout the study.
  • Health related quality of life based on Kids' ITP Tools (KIT) questionnaires will be repeated at the end of study period.
  • Assessment of soluble form of glycoprotein VI using sandwich enzyme-linked immunosorbent assay (ELISA) as well as assessment of platelet activation by GPVI using flowcytometry (Gardiner, etal.,2010 ) at baseline and at the end of 6 months treatment period

Statistical Analysis : Analysis of data will be done using Statistical Program for Social Science version 21 (SPSS Inc., Chicago, IL, USA).

Study Type

Interventional

Enrollment (Actual)

36

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Cairo, Egypt, 11579
        • Ainshams University , Faculty of medicine , Pediatric Hematology&Oncology unit, children hospital.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 1 to ≤ 18 years at enrollment. Patient should be able to swallow tablet form. Weight should be ≥ 12kg.
  • Diagnosis of persistent (3-<12 months duration) or chronic cases (≥12 months duration) with day 1 platelet count ≤ 20x10^9.
  • Patients have a bleeding score grade 3 for skin and/or grade 2 or higher for mucosal domains and/or higher than grade 1 for organ domain at the baseline visit or the worst bleeding incident episode in the patient's medical reports in the last 3 months prior screening, using ITP-BAT (v1.0) score.
  • Normal Kidney function tests and liver function tests.

Exclusion Criteria:

  • Acute thrombocytopenic purpura patients or Other causes of thrombocytopenia. Patients with Evans syndrome
  • Hypertension, cardiovascular disease, diabetes, hepatitis C virus (HCV), HIV, hepatitis B surface antigen(HBsAg) seropositive status.
  • Baseline bone marrow biopsy with evident fibrosis (reticulin stain grade 2 or more)
  • Patients who have previously received eltrombopag.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: group 1 Eltrombopag arm

Group 1 (eltrombopag arm n=20 patients): Patients who showed no response (platelet count ≤ 20x109/L) initially for 3 months or relapse after 6 months after at least one prior ITP therapy. patients will receive a total daily dose of eltrombopag of (25-50mg/d). Dose adjustments may be made based on platelets count with an increment of 25mg once per day at 2 weeks intervals (Maximum dose: 75 mg orally once a day).

Patients, who responded poorly to eltrombopag in 6 months or developed adverse effects, were asked to discontinue the medication. Those who responded were followed for further 6 month period.
Drug: Eltrombopag
Patients who showed no response (platelet count ≤ 20x109/L) initially for 3 months or relapse after 6 months after at least one prior ITP therapy will receive a total daily dose of eltrombopag of (25-50mg/d)
Other Names:
  • Revolade
Active Comparator: group 2 conventional Treatment

Group 2 (n=20 patients) Patients who are currently receiving other lines of treatment (steroids, IVIG, azathioprine, and rituximab).

patients will continue on the conventional line of treatment
Drug: conventional
Patients who are currently receiving conventional lines of treatment (steroids, IVIG, azathioprine, and rituximab, Mycophenolate mofetil) will continue on the same line of treatment
Other Names:
  • mabthera
  • gammaglobulin
  • cellcept
  • solumedrol
  • imuran

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Expression of glycoprotein VI collagen receptor
Time Frame: at 24 weeks
Percentages of patients achieving increased expression of glycoprotein VI collagen receptor
at 24 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete response or response
Time Frame: at 24 weeks
Percentages of patients achieving Complete response" (CR) defined as any platelet count of 100x109/L at least once throughout the study period in the absence of rescue treatment and those achieving "Response" (R) is defined as any platelet count between 50 and 100x 109/L or doubling of the baseline count at least once throughout the study period
at 24 weeks
Maintenance of response
Time Frame: at 24 weeks
The maximum duration for which a patient continuously maintained a platelet count between 50 and 100x 10*9/L in the absence of rescue treatment.
at 24 weeks
Safety: Number of Patients who will have adverse events
Time Frame: at 24 weeks
Number of Patients who will have adverse events.
at 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nayera Hazaa Elsherif

Investigators

  • Principal Investigator: Azza AG Tantawy, MD, Ain shams university, Faculty of medicine, Pediatric Hematology &Oncology department

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2018

Primary Completion (Actual)

September 1, 2021

Study Completion (Actual)

September 1, 2021

Study Registration Dates

First Submitted

January 20, 2018

First Submitted That Met QC Criteria

January 20, 2018

First Posted (Actual)

January 26, 2018

Study Record Updates

Last Update Posted (Actual)

October 28, 2021

Last Update Submitted That Met QC Criteria

October 26, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GPVI-ITP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

Still investigators did not decide about sharing individual participants data

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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