Immune Thrombocytopenia
Conditions
Keywords
ITP
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.
Interventions
DRUGEltrombopag
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.
DRUGRomiplostim
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
OTHERhealthy controls
single blood draw for all measures included in the intervention arms
Sponsors
GlaxoSmithKline
Weill Medical College of Cornell University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
10 patients on eltrombopag and 3 were then treated with romiplostim 10 healthy controls
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL | platelet counts on days 8 and 15 | 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 | platelet counts on days 8 and 15 | 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
| Measure | Time frame | Description |
|---|---|---|
| How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | on days 8 and 15 | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline After Eltrombopag Treatment of Platelet Parameters | testing on days 8 and 15 | 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 |
Countries
United States
Participant flow
Recruitment details
patients with persistent or chronic ITP willing to undergo washout period and then multiple visits (7) in 2 weeks period including 3 larger blood draws
Participants by arm
| Arm | Count |
|---|---|
| Eltrombopag Arm Participants will be treated with eltrombopag 75 mg once daily. Participants will be monitored three times a week for the first two weeks, and then monitored as clinically indicated as they continue eltrombopag dosing for four months. | 7 |
| Eltrombopag Receiving Romiplostim Three Participants who had been on eltrombopag in the past will undergo a washout period and will be treated with Romiplostim 10 ug/kg/weekly for 2 weeks. Participants on Romiplostim will be monitored three times a week for two weeks. | 3 |
| Healthy Volunteers single blood draw in healthy volunteers (controls) | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Eltrombopag Arm | Eltrombopag Receiving Romiplostim | Healthy Volunteers | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 10 Participants | 15 Participants |
| Region of Enrollment United States | 7 participants | 3 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 3 | 0 / 10 |
| other Total, other adverse events | 1 / 10 | 0 / 3 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 3 | 0 / 10 |
Outcome results
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
Time frame: platelet counts on days 8 and 15
Population: 0 participants were analyzed in the healthy control arm because healthy controls did not have any blood draws on day 8 and 15 or receive the intervention and hence data was not collected for these participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag Arm | Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL | pts with platelet counts > 50,000/uL on day 8 | 6 participants |
| Eltrombopag Arm | Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL | Pts with platelet counts > 50,000/uL on day 15 | 6 participants |
| Eltrombopag Then Romiplostim | Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL | pts with platelet counts > 50,000/uL on day 8 | 3 participants |
| Eltrombopag Then Romiplostim | Number of Patients for Whom Eltrombopag Increases the Platelet Count to > 50,000/uL | Pts with platelet counts > 50,000/uL on day 15 | 3 participants |
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
Time frame: platelet counts on days 8 and 15
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag Arm | Number of Patients Who Received Romiplostim and Increased Their Platelet Counts to > 50,000/uL | plt cts > 50,000/uL on day 8 | 3 participants |
| Eltrombopag Arm | Number of Patients Who Received Romiplostim and Increased Their Platelet Counts to > 50,000/uL | plt cts > 50,000/uL on day 15 | 3 participants |
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
Time frame: on days 8 and 15
Population: 0 participants were analyzed in the healthy controls arm because healthy controls did not have any blood draw on day 8 and 15 or receive the intervention and hence data was not collected for these participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag Arm | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with Abnl LFTs on day 8 | 1 participants |
| Eltrombopag Arm | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients Abnl LFTs on day 15 | 1 participants |
| Eltrombopag Arm | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with an SAE on day 8 | 0 participants |
| Eltrombopag Arm | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with an SAE on day 15 | 0 participants |
| Eltrombopag Then Romiplostim | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with an SAE on day 15 | 0 participants |
| Eltrombopag Then Romiplostim | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with Abnl LFTs on day 8 | 0 participants |
| Eltrombopag Then Romiplostim | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients with an SAE on day 8 | 0 participants |
| Eltrombopag Then Romiplostim | How Many Patients Developed SAEs and/or Abnormal Liver Tests to a Level > 2 Times the Upper Limit of Normal | number of patients Abnl LFTs on day 15 | 0 participants |
Other Pre-specified
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
Time frame: testing on days 8 and 15
Population: 0 participants were analyzed in the healthy controls arm because healthy controls did not have any blood draw on day 8 and 15 or receive the intervention and hence data was not collected for these participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | platelet apoptosis increase on day 8 | 7 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | platelet apoptosis increase on day 15 | 2 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in intracellular AKT intermediates day 8 | 7 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in intracellular AKT intermediates day 15 | 0 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in A-IPF day 8 | 7 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in A-IPF day 15 | 7 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in large platelets day 8 | 7 Participants |
| Eltrombopag Arm | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in large platelets day 15 | 7 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in large platelets day 15 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | platelet apoptosis increase on day 8 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in A-IPF day 8 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | platelet apoptosis increase on day 15 | 0 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in large platelets day 8 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in intracellular AKT intermediates day 8 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in A-IPF day 15 | 3 Participants |
| Eltrombopag Then Romiplostim | Change From Baseline After Eltrombopag Treatment of Platelet Parameters | increase in intracellular AKT intermediates day 15 | 1 Participants |