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Eltrombopag and the Bcl-extra-large (xL) Pathway in Idiopathic Thrombocytopenic Purpura (ITP)

Primary Purpose

Immune Thrombocytopenia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Eltrombopag
Romiplostim
healthy controls
Sponsored by
Weill Medical College of Cornell University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Immune Thrombocytopenia focused on measuring ITP

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Subject has signed and dated a written informed consent
  • Male or female adults (≥18 years) diagnosed with either primary ITP according to the American Society for Hematology or British Committee for Standards in Haematology (ASH/BCSH) guidelines [Blood, 1996; British Journal of Haematology, 2003] for at least three months prior to study entry or with ITP secondary to Evans syndrome, systemic lupus erythematosus (SLE), or Common Variable Immunodeficiency (including hypogammaglobulinemia).
  • Subjects must have responded with a platelet count > 30,000/µL to a previous ITP therapy including thrombopoietic agents.
  • Platelet count < 30,000/µL
  • Female subjects of childbearing potential are practicing an acceptable method of contraception or are completely abstinent from intercourse.

Exclusion Criteria:

  • Active infection
  • Previously treated with thrombopoietic agents IF either no response at a therapeutic dose (peak platelet count < 50k) OR treatment with the agent within the past 4 weeks
  • Currently treated with concomitant ITP medication that has not been stable in dose for at least 2 weeks - only prednisone, azathioprin, and danazol are allowed.
  • Female subjects who are nursing or pregnant
  • Thrombosis of any kind within past 6 months or on blood thinners because of thrombosis.
  • Intravenous Immunoglobulin (IVIG), IV anti-D, bolus corticosteroids or vinca alkaloids within the past week
  • Other cytotoxic or immunosuppressive ITP therapy within the past 8 weeks or rituximab within the past 12 weeks
  • Active non-dermatologic malignancy defined as presence of known tumor ie. visible by radiography or evident on blood or bone marrow testing OR receiving chemotherapy within past 2 months
  • Hemoglobin < 10 gm/dl or white blood cell count < 2,500/ul
  • Liver function tests (ALT, Aspartate Aminotransferase (AST), or total bilirubin) > three times upper limit of normal (ULN)
  • Creatinine > two times upper limit of normal (ULN)

Sites / Locations

  • Weill Cornell Medical College

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Sham Comparator

Arm Label

eltrombopag

romiplostim

healthy controls

Arm Description

10 ITP patients were treated with daily oral eltrombopag 75mg for 2 weeks and complete testing was done at weekly intervals 3 times they then were allowed to receive long-term eltrombopag

3 of the patients who received eltrombopag were also treated with romiplostim 10 micrograms/kg weekly for 2 weeks with the same complete testing done at weekly intervals three times after a washout period > 1 month they then resumed long-term eltrombopag

no intervention single blood draw with complete studies

Outcomes

Primary Outcome Measures

Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL
number of patients in whom Platelet Counts measured on days 8 and 15 after eltrombopag treatment increase to > 50,000/uL counts on other days are just used to be sure the ones on days 8 and 15 are reasonably accurate and representative
Number of Patients Who Received Romiplostim and Increased Their Platelet Counts to > 50,000/uL
number of participants in whom platelet counts measured on day 8 and day 15 after treatment(s) with romiplostim 10 micrograms/kg on days 1 and 8

Secondary Outcome Measures

How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal
To assess the safety of eltrombopag, in particular the number of patients with serious adverse events and/or abnormal liver tests reaching a level of more than twice the upper limit of normal for the test these outcomes were assessed periodically for liver tests but other SAEs were not systematically assessed but only with complaints or events

Full Information

First Posted
May 8, 2009
Last Updated
March 15, 2019
Sponsor
Weill Medical College of Cornell University
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT00902018
Brief Title
Eltrombopag and the Bcl-extra-large (xL) Pathway in Idiopathic Thrombocytopenic Purpura (ITP)
Official Title
The Effect of Eltrombopag on Platelet Survival: the Role of the B-cell L Extra Large (BcL-xL) Pathway
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
January 2009 (undefined)
Primary Completion Date
September 7, 2015 (Actual)
Study Completion Date
September 7, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to further evaluate the effects that eltrombopag (and romiplostim) have on platelets in subjects with chronic ITP. Eltrombopag is approved by the Food and Drug Administration (FDA) for the treatment of low platelets in patients with chronic ITP. It is being further studied by GlaxoSmithKline (now Novartis) in other conditions associated with low platelets. This research study is being done because eltrombopag has been shown to increase platelet counts in a different way than other therapies for ITP. The investigators want to further study how eltrombopag and romiplostim affect subjects and their platelets to determine how the study drug should best be used in ITP treatment.
Detailed Description
The B-cell lymphoma extra large (Bcl-xL/Bak) balance has been identified as an intrinsic mechanism that is critical in determining platelet lifespan (Mason, Cell 2007). There is evidence that Bcl-xL protein expression in megakaryocytes is regulated by Thrombopoietin (TPO) mediated activation of Akt pathways mediated by Jak2 and Stat 5 (possibly by Stat 3 as well). (e.g., Kozuma et. al., Journal of Thrombosis and Haemostasis). Little is known about the Bcl-xL / Bak axis in patients with ITP, or the effect of TPO-R stimulation on platelet survival in patients with ITP. The TPO effect may be a result of stimulation of thrombopoietin-receptor (TPO-R) signalling in megakaryocytes altering the packaging of Bcl-xl into platelets, or be a direct effect of platelet TPO-R stimulation as described above.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Immune Thrombocytopenia
Keywords
ITP

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
10 patients on eltrombopag and 3 were then treated with romiplostim 10 healthy controls
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
eltrombopag
Arm Type
Experimental
Arm Description
10 ITP patients were treated with daily oral eltrombopag 75mg for 2 weeks and complete testing was done at weekly intervals 3 times they then were allowed to receive long-term eltrombopag
Arm Title
romiplostim
Arm Type
Experimental
Arm Description
3 of the patients who received eltrombopag were also treated with romiplostim 10 micrograms/kg weekly for 2 weeks with the same complete testing done at weekly intervals three times after a washout period > 1 month they then resumed long-term eltrombopag
Arm Title
healthy controls
Arm Type
Sham Comparator
Arm Description
no intervention single blood draw with complete studies
Intervention Type
Drug
Intervention Name(s)
Eltrombopag
Other Intervention Name(s)
revolade, promacta
Intervention Description
The 10 subjects will be treated with eltrombopag 75 mg once daily. Patients will be monitored 3 times, weekly, for the first 2 weeks, and then monitored as clinically indicated as they continue eltrombopag dosing for 3-4 months.
Intervention Type
Drug
Intervention Name(s)
Romiplostim
Other Intervention Name(s)
amg531, nplate
Intervention Description
three of the patients treated with eltrombopag will be treated with weekly romiplostim at a dose of 10 micrograms/kg weekly for 2 weeks with testing at weekly intervals for 3 times
Intervention Type
Other
Intervention Name(s)
healthy controls
Other Intervention Name(s)
volunteers not receiving any treatment
Intervention Description
single blood draw for all measures included in the intervention arms
Primary Outcome Measure Information:
Title
Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL
Description
number of patients in whom Platelet Counts measured on days 8 and 15 after eltrombopag treatment increase to > 50,000/uL counts on other days are just used to be sure the ones on days 8 and 15 are reasonably accurate and representative
Time Frame
platelet counts on days 8 and 15
Title
Number of Patients Who Received Romiplostim and Increased Their Platelet Counts to > 50,000/uL
Description
number of participants in whom platelet counts measured on day 8 and day 15 after treatment(s) with romiplostim 10 micrograms/kg on days 1 and 8
Time Frame
platelet counts on days 8 and 15
Secondary Outcome Measure Information:
Title
How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal
Description
To assess the safety of eltrombopag, in particular the number of patients with serious adverse events and/or abnormal liver tests reaching a level of more than twice the upper limit of normal for the test these outcomes were assessed periodically for liver tests but other SAEs were not systematically assessed but only with complaints or events
Time Frame
on days 8 and 15
Other Pre-specified Outcome Measures:
Title
Change From Baseline After Eltrombopag Treatment of Platelet Parameters
Description
Samples were drawn weekly for 2 weeks on days 1, 8, and 15 for the treatment arms and day 1 for the healthy control group. Platelet samples were exposed to small molecule Bcl-xL inhibitor, ABT-737 ex-vivo to explore resistance to apoptosis by determining the half maximal inhibitory concentration (IC50) which was measured for each weekly sample drawn. If the half maximal concentration of ABT737 was increased this meant increased resistance to apoptosis. The AKT pathway intermediates were measured since these would indicate the mechanism of the platelet resistance to apoptosis so the two sets of measures confirm each other the AIPF is a measure of how many new platelets are made and the large platelets are similar to that
Time Frame
testing on days 8 and 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Subject has signed and dated a written informed consent Male or female adults (≥18 years) diagnosed with either primary ITP according to the American Society for Hematology or British Committee for Standards in Haematology (ASH/BCSH) guidelines [Blood, 1996; British Journal of Haematology, 2003] for at least three months prior to study entry or with ITP secondary to Evans syndrome, systemic lupus erythematosus (SLE), or Common Variable Immunodeficiency (including hypogammaglobulinemia). Subjects must have responded with a platelet count > 30,000/µL to a previous ITP therapy including thrombopoietic agents. Platelet count < 30,000/µL Female subjects of childbearing potential are practicing an acceptable method of contraception or are completely abstinent from intercourse. Exclusion Criteria: Active infection Previously treated with thrombopoietic agents IF either no response at a therapeutic dose (peak platelet count < 50k) OR treatment with the agent within the past 4 weeks Currently treated with concomitant ITP medication that has not been stable in dose for at least 2 weeks - only prednisone, azathioprin, and danazol are allowed. Female subjects who are nursing or pregnant Thrombosis of any kind within past 6 months or on blood thinners because of thrombosis. Intravenous Immunoglobulin (IVIG), IV anti-D, bolus corticosteroids or vinca alkaloids within the past week Other cytotoxic or immunosuppressive ITP therapy within the past 8 weeks or rituximab within the past 12 weeks Active non-dermatologic malignancy defined as presence of known tumor ie. visible by radiography or evident on blood or bone marrow testing OR receiving chemotherapy within past 2 months Hemoglobin < 10 gm/dl or white blood cell count < 2,500/ul Liver function tests (ALT, Aspartate Aminotransferase (AST), or total bilirubin) > three times upper limit of normal (ULN) Creatinine > two times upper limit of normal (ULN)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James B. Bussel, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25132654
Citation
Mitchell WB, Pinheiro MP, Boulad N, Kaplan D, Edison MN, Psaila B, Karpoff M, White MJ, Josefsson EC, Kile BT, Bussel JB. Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia. Am J Hematol. 2014 Dec;89(12):E228-34. doi: 10.1002/ajh.23832. Epub 2014 Sep 2.
Results Reference
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Eltrombopag and the Bcl-extra-large (xL) Pathway in Idiopathic Thrombocytopenic Purpura (ITP)

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