Eltrombopag and the Bcl-extra-large (xL) Pathway in Idiopathic Thrombocytopenic Purpura (ITP)
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: eltrombopag 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 |
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.
Other Names:
|
| Experimental: romiplostim 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 |
Drug: 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 Names:
|
| Sham Comparator: healthy controls no intervention single blood draw with complete studies |
Other: healthy controls
single blood draw for all measures included in the intervention arms
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Weill Cornell Medical College | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Weill Medical College of Cornell University
- GlaxoSmithKline
Investigators
- Principal Investigator: James B. Bussel, MD, Weill Medical College of Cornell University
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 0809009980
Study Results
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 |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Eltrombopag | Eltombopag Then Romiplostim | Healthy Volunteer |
|---|---|---|---|
| Arm/Group Description | 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 | patients who receive eltrombopag and then are treated with romiplostim (nplate) to ascertain parallelism between the two agents | one blood draw only |
| Period Title: Overall Study | |||
| STARTED | 7 | 3 | 10 |
| COMPLETED | 7 | 3 | 10 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Eltrombopag Arm | Eltrombopag Receiving Romiplostim | Healthy Volunteers | Total |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | single blood draw in healthy volunteers (controls) | Total of all reporting groups |
| Overall Participants | 7 | 3 | 10 | 20 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
3
42.9%
|
2
66.7%
|
10
100%
|
15
75%
|
| >=65 years |
4
57.1%
|
1
33.3%
|
0
0%
|
5
25%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
3
42.9%
|
2
66.7%
|
8
80%
|
13
65%
|
| Male |
4
57.1%
|
1
33.3%
|
2
20%
|
7
35%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
7
100%
|
3
100%
|
10
100%
|
20
100%
|
Outcome Measures
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Eltrombopag Arm | Eltrombopag Then Romiplostim | Healthy Controls |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | 10 normal volunteers for a single blood draw |
| Measure Participants | 7 | 3 | 0 |
| pts with platelet counts > 50,000/uL on day 8 |
6
85.7%
|
3
100%
|
|
| Pts with platelet counts > 50,000/uL on day 15 |
6
85.7%
|
3
100%
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Romiplostim Treated Patients |
|---|---|
| Arm/Group Description | 3 patients treated with romiplostim 10 micrograms/kg weekly twice with weekly platelet counts on days 1, 8, and 15 |
| Measure Participants | 3 |
| plt cts > 50,000/uL on day 8 |
3
42.9%
|
| plt cts > 50,000/uL on day 15 |
3
42.9%
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Eltrombopag | Romiplostim | Healthy Controls |
|---|---|---|---|
| Arm/Group Description | 10 ITP patients were treated with daily oral eltrombopag 75mg for 2 weeks and testing was done at weekly intervals 3 times they then were allowed to receive long-term eltrombopag Eltrombopag: The 10 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. | 3 patients, who first received eltrombopag, were treated with romiplostim 10 micrograms/kg weekly for 2 weeks with the same testing done at weekly intervals three times 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 and blood counts monitored 3 times per week | healthy controls: single blood draw for all measures included in the intervention arms |
| Measure Participants | 10 | 3 | 0 |
| number of patients with Abnl LFTs on day 8 |
1
14.3%
|
0
0%
|
|
| number of patients Abnl LFTs on day 15 |
1
14.3%
|
0
0%
|
|
| number of patients with an SAE on day 8 |
0
0%
|
0
0%
|
|
| number of patients with an SAE on day 15 |
0
0%
|
0
0%
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Eltrombopag Arm | Eltrombopag Then Romiplostim | Healthy Control Group |
|---|---|---|---|
| Arm/Group Description | 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. | Three Participants were treated identically as per the eltrombopag arm and, several months later, would undergo a second washout period and were treated with Romiplostim 10 ug/kg/weekly for 2 weeks. Participants on Romiplostim will be monitored as were the Eltrombopag participants for 2 weeks. | 10 Control Participants without thrombocytopenia or any major health issues were enrolled to provide laboratory comparison data to the ITP patients with a single blood draw for platelet counts, IPF, large platelets, IC50 for apoptosis, AKT pathway intermediates. |
| Measure Participants | 7 | 3 | 0 |
| platelet apoptosis increase on day 8 |
7
100%
|
3
100%
|
|
| platelet apoptosis increase on day 15 |
2
28.6%
|
0
0%
|
|
| increase in intracellular AKT intermediates day 8 |
7
100%
|
3
100%
|
|
| increase in intracellular AKT intermediates day 15 |
0
0%
|
1
33.3%
|
|
| increase in A-IPF day 8 |
7
100%
|
3
100%
|
|
| increase in A-IPF day 15 |
7
100%
|
3
100%
|
|
| increase in large platelets day 8 |
7
100%
|
3
100%
|
|
| increase in large platelets day 15 |
7
100%
|
3
100%
|
Adverse Events
| Time Frame | 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 | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | patients were asked for concomitant meds and Adverse Events on every visit | |||||
| Arm/Group Title | Eltrombopag | Romiplostim | Healthy Volunteers | |||
| Arm/Group Description | 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. | 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. | single blood draw in healthy controls/volunteers | |||
All Cause Mortality |
||||||
| Eltrombopag | Romiplostim | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/3 (0%) | 0/10 (0%) | |||
Serious Adverse Events |
||||||
| Eltrombopag | Romiplostim | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/3 (0%) | 0/10 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Eltrombopag | Romiplostim | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/10 (10%) | 0/3 (0%) | 0/10 (0%) | |||
| Hepatobiliary disorders | ||||||
| increase in LFTs | 1/10 (10%) | 1 | 0/3 (0%) | 0 | 0/10 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr James Bussel |
|---|---|
| Organization | Weill Cornell Medical College |
| Phone | 22-746-3474 |
| jbussel@med.cornell.edu |
- 0809009980