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| Name | Class |
|---|---|
| GlaxoSmithKline | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| eltrombopag | Experimental | 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 |
|
| romiplostim | Experimental | 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 |
|
| healthy controls | Sham Comparator | no intervention single blood draw with complete studies |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Eltrombopag | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James B. Bussel, MD | Weill Medical College of Cornell University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Weill Cornell Medical College | New York | New York | 10065 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25132654 | Result | 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. |
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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
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| ID | Title | Description |
|---|---|---|
| FG000 | Eltrombopag | Promacta (eltrombopag): Subjects will be treated with eltrombopag 75 mg once daily. Patients will be monitored 3 times a week for the first 2 weeks, and then monitored as clinically indicated as they continue eltrombopag dosing for 3-4 months. first blood draw before taking eltrombopag |
| FG001 | Eltombopag Then Romiplostim | patients who receive eltrombopag and then are treated with romiplostim (nplate) to ascertain parallelism between the two agents |
| FG002 | Healthy Volunteer | one blood draw only |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
10 patients receive eltrombopag and 3 of these go on to receive romiplostim
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Eltrombopag Receiving Romiplostim |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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 | Posted | Number | participants | platelet counts on days 8 and 15 |
|
data for investigation collected over 2 weeks in all patients: 7 with eltrombopag alone and 3 with eltrombopag first and, then after a washout period, romiplostim later this would be 10 for eltrombopag and 3 for romiplostim additional medication provided as incentive to patients to enter the study there was a single blood draw without incident in the 10 healthy volunteers
patients were asked for concomitant meds and Adverse Events on every visit
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Eltrombopag | Ten 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| increase in LFTs | Hepatobiliary disorders | Non-systematic Assessment | increase in ALT/AST |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr James Bussel | Weill Cornell Medical College | 22-746-3474 | jbussel@med.cornell.edu |
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| ID | Term |
|---|---|
| D016553 | Purpura, Thrombocytopenic, Idiopathic |
| ID | Term |
|---|---|
| D011696 | Purpura, Thrombocytopenic |
| D011693 | Purpura |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| C520809 | eltrombopag |
| C488777 | romiplostim |
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10 patients on eltrombopag and 3 were then treated with romiplostim 10 healthy controls
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|
| Romiplostim | Drug | 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 controls | Other | single blood draw for all measures included in the intervention arms |
|
|
| on days 8 and 15 |
| testing on days 8 and 15 |
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. |
| BG002 | Healthy Volunteers | single blood draw in healthy volunteers (controls) |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Eltrombopag Then Romiplostim | Three Participants from Eltrombopag arm will undergo second 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 exactly like when they received Eltrombopag. |
| OG002 | Healthy Controls | 10 normal volunteers for a single blood draw |
|
|
| 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 | Posted | Number | participants | 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 | 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 | Posted | Number | participants | on days 8 and 15 |
|
|
|
| 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 | 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 | Posted | Count of Participants | Participants | testing on days 8 and 15 |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
| EG001 | Romiplostim | Three Participants who had been on eltrombopag 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. | 0 | 3 | 0 | 3 | 0 | 3 |
| EG002 | Healthy Volunteers | single blood draw in healthy controls/volunteers | 0 | 10 | 0 | 10 | 0 | 10 |
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| D006425 |
| Hemic and Lymphatic Diseases |
| D057049 | Thrombotic Microangiopathies |
| D013921 | Thrombocytopenia |
| D001791 | Blood Platelet Disorders |
| D000095542 | Cytopenia |
| D006474 | Hemorrhagic Disorders |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012877 | Skin Manifestations |
| D012816 | Signs and Symptoms |
| number of patients with an SAE on day 8 |
|
| number of patients with an SAE on day 15 |
|
| increase in intracellular AKT intermediates day 8 |
|
| increase in intracellular AKT intermediates day 15 |
|
| increase in A-IPF day 8 |
|
| increase in A-IPF day 15 |
|
| increase in large platelets day 8 |
|
| increase in large platelets day 15 |
|