Safety and Efficacy of Eltrombopag at Escalated Doses
Study rationale is based on the data that in previous clinical studies of eltrombopag in ITP there are some patients who have been reported as non responders at the maximal approved dose of 75 mg daily. The trend in both normal volunteers and in patients with ITP suggest and increasing response rate with increased doses of eltrombopag up to a dose of 75mg. Previously published data has shown no overt increase in toxicity in normal volunteers, oncology patients and aplastic anemia patients treated with escalated doses as high or higher than those proposed in this study.
It therefore seems possible that in ITP patients who did not respond to a dose of 75mg daily, eltrombopag could be more effective at a higher dose. We propose a double blind randomized controlled trial in ITP patients who have been defined as non-responders at the maximum dose (75mg) of eltrombopag, assessing efficacy and toxicity at higher daily doses (100mg, 125 mg, 150 mg)
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Safety and Efficacy of Eltrombopag at Escalated Doses up to 150mg in Patients With Persistent and Chronic Immune Thrombocytopenia (ITP) Not Responsive to 75 mg|
- Proportion of patients responding to >75mg daily [ Time Frame: Evaluated throughout the study. Endpoints will be at 8 weeks of the blinded study and in the open label portion of the study up to 18 months. ] [ Designated as safety issue: No ]To determine the proportion of patients with chronic ITP who do not respond to 75 mg of eltrombopag daily given for at least 3 weeks but then do respond to eltrombopag given daily first for 2 weeks at doses of 100, then for 2 weeks at 125 mg and finally for 4 weeks at a dose of 150mg daily. Dosing will stop if the platelet count exceeds 100,000. Response will be defined as 2 consecutive platelet counts of > 50,000 and an increase of > 20,000 from the study baseline within the 8 week increased dose window not as a result of rescue treatment.
- Efficacy of increased dosage of eltrombopag in ITP patients at doses > 75 [ Time Frame: Evaluated throughout the study. Endpoints will be at 8 weeks of the blinded study and in the open label portion of the study up to 18 months. ] [ Designated as safety issue: No ]To determine efficacy of administration of increased dosage of eltrombopag to subjects with chronic ITP who did not respond to current maximally approved daily dose of 75 mg for at least 3 weeks by measuring: number of weeks of platelet counts of response; number of durable responses here defined as platelet counts of response for 3 weeks among the last 4 weeks; number of patients achieving a platelet count > 100,000 and number of platelet counts per patient > 100,000. (Note if a platelet count > 150,000 is achieved that week and the subsequent weeks of the 8 week study will be considered to all be over 100,000 for purposes of all analyses).
- Evaluating safety in patients receiving doses > 75mg [ Time Frame: up to 18 months. ] [ Designated as safety issue: Yes ]
To determine the safety of administration of increased dosage of eltrombopag to subjects with ITP who did not respond to current maximally approved daily dose of 75 mg for at least 3 weeks.
To evaluate if there are subgroups of patients (despite being underpowered) who are more likely or less likely to either respond or to experience adverse events:Starting platelet counts, splenectomy status, concomitant meds e.g, daily prednisone at a maximum dose of 20mg daily, duration of ITP diagnosis, starting Hemoglobin and Absolute Neutrophil Count (ANC), starting ALTs, bilirubins or Alk Phos levels, Platelet Reticulocyte Count
|Study Start Date:||February 2013|
|Estimated Study Completion Date:||February 2016|
|Estimated Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Active Comparator: Eltrombopag
Subjects in the study will receive 75 mg eltrombopag and then be randomized to receive either an additional 25 mg of eltrombopag or matching placebo tablet dispensed by the research pharmacy. Subjects and investigators will be blinded to randomization. Randomization will be stratified according to splenectomy status. Randomization will be performed at the time of informed consent with a computer generated randomization table. Subjects and investigators will be blinded to assignment and treatment in this phase.
Eltrombopag will be administered for 8 weeks or until the platelet count exceeds 150,000; at this point dosing will stop, subject will be considered a responder and the subject will eligible for entering Part 2 (the long term treatment part of the study. The dose at which the subject achieved the primary endpoint (> 50,000 and increase by > 20,000) will be considered the dose of response. Dose escalation will continue, despite satisfaction of the primary endpoint of study (> 50,000 and > 20,000 above baseline), unless the platelet count reaches the lower limit of normal range 150,000. Subjects will stop study medication if the platelet count is within the normal range, thereby minimizing any safety risk associated with elevated platelet count.
Placebo Comparator: Placebo
Subjects will be randomly allocated in a two to one ratio to receive treatment or placebo. All subjects in the study will receive 75 mg eltrombopag and then be randomized to receive either an additional 25 mg of eltrombopag or matching placebo tablet dispensed by the research pharmacy. Subjects and investigators will be blinded to randomization. Randomization will be stratified according to splenectomy status.
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|Contact: James B Bussel, M.D.||email@example.com|
|United States, New York|
|Weill Cornell Medical College||Recruiting|
|New York, New York, United States, 10065|
|Contact: James B Bussel, M.D. 212-746-3474 Jbussel@med.cornell.edu|
|Principal Investigator: James B Bussel, M.D.|
|Sub-Investigator: Catherine McGuinn, M.D.|
|Principal Investigator:||James B Bussel, M.D.||Weill Medical College of Cornell University|
|Principal Investigator:||Catherine McGuinn, M.D.||Weill Medical College of Cornell University|