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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Number of Patients Responding to >75mg Daily as Defined by a Rise in Platelet Count by 20,000/Microliter, With a Total Platelet Count >50,000/Microliter, ON TWO CONSECUTIVE OCCASIONS During the 8 Week Period
研究概览
简要总结
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)
详细描述
Preliminary data in pediatric patients (who seem to metabolize eltrombopag differently especially at younger ages) find that in the middle and lowest age cohort, even doses of 75 mg were often insufficient to obtain a response.
Altogether, this data suggest both that a higher dose in ITP may be more efficacious in increasing the platelet count and that there is no overt increase in toxicity in normal volunteers, oncology patients and aplastic anemia patients treated with doses as high or higher than those proposed in this study.
Double-blind, randomized, placebo-controlled trial in subjects with ITP who are 'non-responders' at the maximum package insert dose (75mg) of eltrombopag; non-responders are those with platelet counts < 50,000 despite taking 75 mg/day of eltrombopag for at least 3 weeks.
Study Design (First part): 8 Weeks
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. 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 100,000; 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) if desired and agreed to be appropriate by the subject giving consent, and the treating physician. The dose at which the subject achieved the primary endpoint (> 50,000 and increase by > 20,000) will be considered the dose of response. Even if a patient achieves a response, if the platelet counts remains < 100,000, then the dose escalation schema in the figure above will continue.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject or their parent/ guardian has signed and dated a written informed consent
- •Male and Females aged 12 years or older diagnosed with chronic ITP according to the new consensus guidelines
- •No indication of a disease which may cause thrombocytopenia other than ITP----no specific testing required
- •Subjects with thrombocytopenia ≤ 50,000 /uL after at least 21 days of daily dosage with eltrombopag 75mg
- •Stable dosage of concomitant treatments for ITP
- •≥ 2 weeks or longer (corticosteroids);
- •At least 2 weeks from rescue therapy for ITP (WinRho, Intravenous Immunoglobulin (IVIG), corticosteroids, platelet transfusion)
- •At least 4 weeks from rituximab treatment
- •Pregnant or Lactating Women are excluded
- •Women of child-bearing age with a negative pregnancy test within 7 days of enrollment and who agree to use acceptable methods of birth control will be eligible for this study
- •Female subjects or female partners of male subjects must either be of non-child bearing potential (hysterectomy, bilateral ovariectomy, bilateral tubal ligation or post menopausal for more than one year) OR, if of child bearing potential, using one of the following highly effective methods of contraception.
- •complete abstinence from intercourse
- •Intrauterine device (IUD)
- •Two forms of barrier contraception. diaphragm plus spermicide, or for males condoms plus spermicide.
- •Male partner is sterile and is the only partner of the female.
- •Systemic contraceptives (combined oral progesterone only)
排除标准
- •Previous history of eltrombopag-related liver function test (LFT) elevation that required interruption of treatment
- •Previous history of immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag
- •HIV Infection
- •History of Arterial of Venous Thrombosis within the past year or requiring ongoing therapy
- •Active Hepatitis C infection
- •Treatment with medications that affect platelet function ( including but not limited to Aspirin, Clopidogrel and /or NSAIDs) or anti-coagulant medications
- •Elevated Aspartate Aminotransferase(AST/ALT) or Creatinine > 1.5 times upper limit of normal in 4 weeks prior to enrollment*
- •Abnormalities in white blood cell count (WBC), automatic neutrophil count (ANC), and Hemoglobin > 1.5 times upper or lower limit of normal*
- •* Subjects can be rescreened to be included
研究组 & 干预措施
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.
干预措施: Eltrombopag (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Patients Responding to >75mg Daily as Defined by a Rise in Platelet Count by 20,000/Microliter, With a Total Platelet Count >50,000/Microliter, ON TWO CONSECUTIVE OCCASIONS During the 8 Week Period
时间窗: 8 weeks
To determine if 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. Response will be defined as 2 consecutive platelet counts of \> 50,000 with an increase of \> 20,000 from the study baseline within the 8 week increased dose window not as a result of rescue treatment.
次要结局
- Number of Particiapants With Drug Related Adverse Events(8 weeks)