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

Phase 2CompletedNCT00902018

Weill Medical College of Cornell University20 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Interventions

EltrombopagDRUG

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.

RomiplostimDRUG

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

healthy controlsOTHER

single blood draw for all measures included in the intervention arms

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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

Time frame: platelet counts on days 8 and 15

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

Time frame: platelet counts on days 8 and 15

Secondary Outcomes

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

Time frame: on days 8 and 15