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

• ClinicalTrials.gov Identifier: NCT03412188
• Recruitment Status: Recruiting
• First Posted: January 26, 2018
• Last Update Posted: August 14, 2018
• Sponsor: Nayera Hazaa Elsherif
• Information provided by (Responsible Party): Nayera Hazaa Elsherif, Ain Shams University

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
Idiopathic Thrombocytopenic Purpura	Drug: Eltrombopag; Drug: conventional	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• 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
• Official Title: 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.
• Actual Study Start Date: August 1, 2018
• Estimated Primary Completion Date: November 2019
• Estimated Study Completion Date: November 2019

Arms and Interventions

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 Name: 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: solumedrol; imuran; cellcept; mabthera; gammaglobulin

Outcome Measures

Primary Outcome Measures :

1. Expression of glycoprotein VI collagen receptor [ Time Frame: at 24 weeks ]
   Percentages of patients achieving increased expression of glycoprotein VI collagen receptor

Secondary Outcome Measures :

1. 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
2. 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.
3. Safety: Number of Patients who will have adverse events [ Time Frame: at 24 weeks ]
   Number of Patients who will have adverse events.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: nayera elsherif, MD; 01003322052; elsherif.nayera@gmail.com

Contact: fatma ebeid, MD; 01095569596; dr.fatma_ebeid@yahoo.com

Locations

Egypt

Ainshams University , Faculty of medicine , Pediatric Hematology&Oncology unit, children hospital.; Recruiting

Cairo, Egypt, 11579

Contact: Micheal morcos, M.Sc mekoo_828@yahoo.com

Contact: Mahmoud Kenny, MD moudykenny@yahoo.com

Principal Investigator: Azza AG Tantawy, MD

Sub-Investigator: Nayera HK El Sherif, MD

Sub-Investigator: Fatma S Ebeid, MD

Sub-Investigator: Eman AR Ismail, MD

Sub-Investigator: Mahmoud A Kenny, MD

Sub-Investigator: Michael BE morcos, M.Sc

Sponsors and Collaborators

Nayera Hazaa Elsherif

Investigators

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

More Information

Publications of Results:

Buchanan GR. Overview of ITP treatment modalities in children. Blut. 1989 Jul;59(1):96-104. Review.

Bussel JB, de Miguel PG, Despotovic JM, Grainger JD, Sevilla J, Blanchette VS, Krishnamurti L, Connor P, David M, Boayue KB, Matthews DC, Lambert MP, Marcello LM, Iyengar M, Chan GW, Chagin KD, Theodore D, Bailey CK, Bakshi KK. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015 Aug;2(8):e315-25. doi: 10.1016/S2352-3026(15)00114-3. Epub 2015 Jul 28. Erratum in: Lancet Haematol. 2015 Oct;2(10):e407.

Chiou TJ, Chang YF, Wang MC, Kao CW, Lin HY, Chen TY, Hsueh EJ, Lan YJ, Sung YC, Lin SF, Bai LY, Chen CG. Eltrombopag enhances platelet adhesion by upregulating the expression of glycoprotein VI in patients with chronic immune thrombocytopenic purpura. Transl Res. 2015 Dec;166(6):750-761.e4. doi: 10.1016/j.trsl.2015.09.005. Epub 2015 Sep 30.

Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002 Mar 28;346(13):995-1008. Review.

Ehrlich LA, Kwitkowski VE, Reaman G, Ko CW, Nie L, Pazdur R, Farrell AT. U.S. Food and Drug Administration approval summary: Eltrombopag for the treatment of pediatric patients with chronic immune (idiopathic) thrombocytopenia. Pediatr Blood Cancer. 2017 Dec;64(12). doi: 10.1002/pbc.26657. Epub 2017 Jun 19.

Gardiner EE, Andrews RK. Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI. Transfus Med Rev. 2014 Apr;28(2):56-60. doi: 10.1016/j.tmrv.2014.03.001. Epub 2014 Mar 12. Review.

Gardiner EE, Thom JY, Al-Tamimi M, Hughes A, Berndt MC, Andrews RK, Baker RI. Restored platelet function after romiplostim treatment in a patient with immune thrombocytopenic purpura. Br J Haematol. 2010 May;149(4):625-8. doi: 10.1111/j.1365-2141.2010.08092.x. Epub 2010 Feb 8.

Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. doi: 10.1016/S0140-6736(15)61107-2. Epub 2015 Jul 28. Erratum in: Lancet. 2015 Oct 24;386(10004):1630.

Holmes ML, Bartle N, Eisbacher M, Chong BH. Cloning and analysis of the thrombopoietin-induced megakaryocyte-specific glycoprotein VI promoter and its regulation by GATA-1, Fli-1, and Sp1. J Biol Chem. 2002 Dec 13;277(50):48333-41. Epub 2002 Sep 30.

Klaassen RJ, Blanchette VS, Barnard D, Wakefield CD, Curtis C, Bradley CS, Neufeld EJ, Buchanan GR, Silva MP, Chan AK, Young NL. Validity, reliability, and responsiveness of a new measure of health-related quality of life in children with immune thrombocytopenic purpura: the Kids' ITP Tools. J Pediatr. 2007 May;150(5):510-5, 515.e1.

Rodeghiero F, Michel M, Gernsheimer T, Ruggeri M, Blanchette V, Bussel JB, Cines DB, Cooper N, Godeau B, Greinacher A, Imbach P, Khellaf M, Klaassen RJ, Kühne T, Liebman H, Mazzucconi MG, Newland A, Pabinger I, Tosetto A, Stasi R. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood. 2013 Apr 4;121(14):2596-606. doi: 10.1182/blood-2012-07-442392. Epub 2013 Jan 29.

Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kühne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.

Yun SH, Sim EH, Goh RY, Park JI, Han JY. Platelet Activation: The Mechanisms and Potential Biomarkers. Biomed Res Int. 2016;2016:9060143. doi: 10.1155/2016/9060143. Epub 2016 Jun 15. Review.

Meletis J, Katsandris A, Raptis SD, Mantzourani M. Successful treatment of Immune Thrombocytopenic Purpura (ITP) with the thrombopoietin-mimetic romiplostim. Med Sci Monit. 2010 Aug;16(8):CS100-2.

Other Publications:

Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31.

• Responsible Party: Nayera Hazaa Elsherif, assistant professor of pediatrics, Ain Shams University
• ClinicalTrials.gov Identifier: NCT03412188
• Other Study ID Numbers: GPVI-ITP
• First Posted: January 26, 2018
• Last Update Posted: August 14, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Still investigators did not decide about sharing individual participants data

• 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

Keywords provided by Nayera Hazaa Elsherif, Ain Shams University:

Chronic ITP; persistent ITP; Eltrombopag; GPVI receptor

Additional relevant MeSH terms:

Thrombocytopenia; Immune System Diseases; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic; Blood Coagulation Disorders; Hematologic Diseases; Hemorrhage; Pathologic Processes; Skin Manifestations; Signs and Symptoms; Thrombotic Microangiopathies; Blood Platelet Disorders; Hemorrhagic Disorders; Autoimmune Diseases; Azathioprine; gamma-Globulins; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents