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

Immune Thrombocytopenia Clinical Trial

Official title:

The Effect of Eltrombopag on Platelet Survival: the Role of the B-cell L Extra Large (BcL-xL) Pathway

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00902018
• Other study ID #: 0809009980
• Status: Completed
• Phase: Phase 2
• Start date: January 2009
• Est. completion date: September 7, 2015

Study information

• Verified date: March 2019
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: September 7, 2015
• Est. primary completion date: September 7, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Immune Thrombocytopenia
• Purpura, Thrombocytopenic, Idiopathic
• Thrombocytopenia

Intervention

Drug:
• Eltrombopag
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.
• Romiplostim
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

Other:
• healthy controls
single blood draw for all measures included in the intervention arms

Locations

Country	Name	City	State
United States	Weill Cornell Medical College	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline After Eltrombopag Treatment of Platelet Parameters	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	testing on days 8 and 15
Primary	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	platelet counts on days 8 and 15
Primary	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	platelet counts on days 8 and 15
Secondary	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	on days 8 and 15

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