The Effect of Eltrombopag on the Expression of Platelet Collagen Receptor GPVI in Pediatric ITP.
Condition: Idiopathic Thrombocytopenic Purpura
MeSH terms: Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic
Study type: Interventional

Summary: 
      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
    

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).
    

Intervention name(s): Eltrombopag; conventional
Intervention type(s): Drug; Drug
Intervention description(s): 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); 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 intervention name(s): Revolade; solumedrol; imuran; cellcept; mabthera; gammaglobulin
Intervention MeSH terms: Methylprednisolone Hemisuccinate; gamma-Globulins
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be divided into 2 groups:
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.
Group 2 (n=20 patients) Patients who are currently receiving other lines of treatment (steroids, IVIG, azathioprine, and rituximab).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic ITP; persistent ITP; Eltrombopag; GPVI receptor