NCT00908037已完成2 期
A Three Part, Staggered Cohort, Open-label and Double Blind, Randomized, Placebo Controlled Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of Eltrombopag, a Thrombopoietin Receptor Agonist, in Previously Treated Pediatric Patients With Chronic ITP.
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 82
- 试验地点
- 1
- 主要终点
- Percentage of Participants Achieving a Platelet Count >=50 Giga Cells Per Liter (Gi/L) at Least Once, Between Day 8 and Day 43 (Weeks 1 to 6) of the Randomized Period of the Study (Part 2)
研究概览
简要总结
Phase II, multi-center, 3 part, staggered cohort, open-label and double blind, randomized, placebo controlled study involving 3 age-determined cohorts (Cohort 1: between 12 and 17 years old; Cohort 2: between 6 and 11 years old; Cohort 3: between 1 and 5 years old). Daily dosing with eltrombopag will begin with 5 patients in the oldest age cohort in an open label fashion, and a review of safety, pharmacokinetic and platelet count data will be performed regularly. If no safety concerns are identified after 12 weeks, 18 additional patients will be randomised to placebo or eltrombopag (2:1 randomisation). After 7 weeks of randomized treatment, all patients will receive eltrombopag in an open label fashion. The total duration of treatment with eltrombopag will be 24 weeks. If at the time of the aforementioned 12 week review of the first 5 patients no safety issues are identified, dosing will begin in the next lower age cohort with an initial group of 5 patients. The same procedure will be followed in terms of safety review and subsequent enrolment and randomisation of the additional patients. Initiation of the younger age cohort will take place once data from the previous has been evaluated. Doses will be adjusted according to platelet counts and tolerability. The study will include a review of the safety data by a Data Safety Monitoring Board.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 1 Year 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects between 1 year and <18 years of age at Day
- •Written informed consent from subject's guardian and accompanying informed assent from subject (for children over 6 years old).
- •Confirmed diagnosis of chronic ITP, according to the American Society of Hematology / British Committee for Standards in Haematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003]. In addition, a peripheral blood smear or bone marrow examination should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia.
- •Subjects who are refractory or have relapsed after at least one prior ITP therapy or are not eligible, for a medical reason, for other treatments.
- •Day 1 (or within 48 hours prior) platelet count <30 Gi/L.
- •Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 2 weeks prior to Day 1 or have been clearly ineffective.
- •Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to Day
- •Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to Day 1 or have clearly been ineffective.
- •Subjects must have prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) within 80 to 120% of the normal range.
- •Subjects must have a complete blood count (CBC) not suggestive of another hematological disorder.
- •The following clinical chemistries for the subjects MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%.
- •For subjects of child-bearing potential (after menarche): subject must not be sexually active or is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must use one of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:
- •Complete abstinence from intercourse;
- •Intrauterine device (IUD);
- •Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);
- •Systemic contraceptives (combined or progesterone only).
排除标准
- •Any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g. thrombocytopenia is secondary to another disease).
- •Concurrent or past malignant disease, including myeloproliferative disorder.
- •Subjects who are not suitable for continuation of their current therapy for at least 7 additional additional weeks.
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day
- •History of platelet agglutination abnormality that prevents reliable measurement of platelet counts.
- •Diagnosis of secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence of active hepatitis at the time of subject screening.
- •Subject with Evans syndrome (autoimmune thrombocytopenia and autoimmune hemolysis).
- •Subjects with known inherited thrombocytopenia (e.g. MYH-9 disorders)
- •Subjects treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for >3 consecutive days within 2 weeks of Day
- •Subjects who have previously received eltrombopag or any other thrombopoietin receptor agonist.
- •For female subjects who have reached menarche status, an inability or unwillingness to provide a blood or urine specimen for pregnancy testing.
- •Female subjects who are pregnant or lactating.
研究组 & 干预措施
placebo plus standard of care
Placebo Comparator
placebo
干预措施: Placebo (Drug)
eltrombopag plus standard of care
Experimental
eltrombopag
干预措施: eltrombopag (Drug)
结局指标
主要结局
Percentage of Participants Achieving a Platelet Count >=50 Giga Cells Per Liter (Gi/L) at Least Once, Between Day 8 and Day 43 (Weeks 1 to 6) of the Randomized Period of the Study (Part 2)
时间窗: From Day 8 up to Day 43 of Part 2
Participants who achieved a platelet count \>=50 Gi/L at least once between Day 8 and Day 43 (first 6 weeks of Part 2) in the absense of rescue treatment were reported. A 95% confidence interval was calculated by the exact binomial method.
次要结局
- Percentage of Participants Achieving Platelet Counts >=50Gi/L at Any Time During the 24 Weeks of Eltrombopag Dosing During Part 1.(From Day 1 of treatment up to Week 24 of Part 1)
- Percentage of Participants Achieving Platelet Counts >=50Gi/L During Treatment With Eltrombopag in >= 60% of Assessments Between Day 15 and Day 43 (Weeks 2 Through 6) of the Randomized Treatment Period (Part 2)(Between Day 15 and Day 43 of Part 2)
- Population Pharmacokinetic (PK) Assessments for Eltrombopag for Tmax During Part 1, 2, and 2/3(From Day 1 of treatment up to Study Week 31)
- Maximum Duration for Which a Participant Continuously Maintained a Platelet Count of >=50 Gi/L During the 7 Weeks of Eltrombopag Treatment in Part 2(From Baseline through Week 7 of Part 2)
- Weighted Mean Platelet Count(Baseline and Day 43 of Part 2)
- Percentage of Participants Achieving Platelet Counts >=50 Gi/L at Any Time During the 31 Weeks of Eltrombopag Treatment During Part 2/ 3.(Part 2/3 up to Study Week 31)
- Kids' ITP Tool (KIT) Questionnaire Total Score at Baseline, Week 6, Week 12, and Week 24 as Assessed Using the KIT Questionnaire During the Dose Finding Period, Part 1(Baseline, Week 6, Week 12, and Week 24 of Part 1)
- Number of Participants With the Indicated Hematology Parameters Falling Outside of the Reference Range at Any Time Post-Baseline During Part 1, Part 2, and Part 2/3(Post-Baseline from Week 1 through Follow-up up to Study Week 35)
- Number of Participants With a Positive Urine Microscopy Parameters Any Time Post-Baseline During Part 2(From Baseline and post-Baseline up to Study Week 7 of Part 2)
- Population Pharmacokinetic (PK) Assessment for Eltrombopag for AUC(0-t) During Part 1, 2, and 2/3.(From Day 1 of treatment up to Study Week 31)
- Number of Participants With Any Bleeding, no Clinically Significant Bleeding and Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale During Part 2/3(From Baseline of Part 2/3 through Follow-up)
- Number of Participants With a Positive Urine Microscopy Parameters Any Time Post-Baseline During Part 1(From Baseline up to Study Week 24 of Part 1)
- Number of Participants With a Positive Urine Microscopy Parameters Any Time Post-Baseline During Part 2/3(From Baseline and post-Baseline up to Study Week 31 of Part 2/3)
- Mean Respiratory Rate at Baseline and Maximum Post-Baseline Visit During Part 2/3(From Week 1 to Follow-up Week 4 of Part 2/3 up to Study Week 35)
- Mean Pulse Rate at Baseline and the Maximum Post-Baseline Visit Recorded During the Randomized Period, Part 2(From Week 1 to Week 7 of Part 2)
- Population Pharmacokinetic (PK) Assessments for Eltrombopag for Cmax and Ct During Part 1, 2, and 2/3.(From Day 1 of treatment up to Study Week 31)
- Population Pharmacokinetic (PK) Assessments for Eltrombopag for CL/F During Part 1, 2, and 2/3(From Day 1 of treatment up to Study Week 31)
- Maximum Duration for Which a Participant Continuously Maintained a Platelet Count of >=50 Gi/L During the 24 Weeks of Eltrombopag Treatment in Part 2/ 3(From Baseline up to Study Week 31)
- Mean Pulse Rate at Baseline and the Maximum Post-Baseline Visit Recorded During the Eltrombopag Only Period Part 2/3(From Week 1to Follow-up Week 4 of Part 2/3, up to Study Week 35)
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During Part 1(From Treatment + 1 day up to Week 24 of Part1)
- Percentage of Participants Who Reduced or Discontinued Baseline Concomitant Idiopathic Thrombocytopenic Purpura (ITP) Medications During the 24 Weeks of Eltrombopag Treatment During Part 1.(From Baseline up to Week 24+ 1 day of Part 1)
- Number of Participants With Any Bleeding, no Clinically Significant Bleeding and Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale During Part 2(From Baseline through Week 7 of Part 2)
- Number of Participants With the Indicated Clinical Chemistry Parameter Falling Outside of the Reference Range Any Time Post-Baseline During Part 1, Part 2, and Part 2/3(Post-Baseline from Week 1 through Follow-up up to Study Week 35)
- Percentage of Participants Who Reduced or Discontinued Baseline Concomitant ITP Medications During the 24 Weeks of Eltrombopag Treatment During Part 2/ 3(From Baseline to the end of treatment up to Week 31 + 1 day of Part 2/3)
- Number of Participants Who Required a Protocol-defined Rescue Treatment During Part 2/3(From Baseline to the end of treatment up to Week 31 + 1 day of Part2/3)
- Kids' ITP Tool (KIT) Questionnaire Total Score at Baseline and Week 6as Assessed Using the KIT Questionnaire During the Randomized Period, Part 2(Baseline and Week 6 of Part 2)
- Kids' ITP Tools (KIT) Questionnaire Total Score at Baseline, Week, 6, Week 12, and End of Treatment Visit as Assessed Using the KIT Questionnaire During the Eltrombopag Open-Label Period, Part 2/3(From Baseline to end of treatment up to Study Week 31)
- Number of Participants With the Indicated Renal Parameters Falling Outside of the Reference Range Any Time Post-Baseline During Part 1, Part 2, and Part 2/3(Post-Baseline from Week 1 through Follow-up up to Study Week 35)
- Number of Participants With the Indicated Vital Signs Falling Outside of the Reference Range During Part 1, Part 2, and Part 2/3(From Baseline through Study Week 35)
- Mean Respiratory Rate at Baseline and the Maximum Post-Baseline Value Recorded During the Dose-Finding Period, Part 1(From Baseline through Week 24)
- Mean Pulse Rate at Baseline and the Maximum Post-Baseline Visit Recorded During the Dose-Finding Period, Part 1(From Week 1 to Follow-up Week 4 of Part 1, up to Study Week 28)
- Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick at Baseline and Week 7 During the Randomized Period,Part 2(Baseline and Week 7 of Part 2)
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During Part 2/3(From Treatment + 1 day up to Week 31 of Part2/3)
- Number of Participants With a Change in Visual Acuity and a Change Due to Worsening of Cataracts(BL, 3 and 6mo Follow-up of Part 2/3)
- Mean Respiratory Rate at Baseline and the Maximum Post-Baseline Value Recorded During the Randomized Period, Part 2(From Week 1 to Week 7 of Part 2)
- Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick at Baseline and Week 24 During the Dose-Finding Period, Part 1(Baseline and Week 24 of Part 1)
- Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick at Baseline and Week 24 During the Eltrombopag Open-label Period, Part 2/3(Baseline and Week 24 of Part 2/3 up to Study Week 31)
- Number of Participants With a Change in Visual Acuity and a Change Due to Worsening of Cataracts During Part 1(Baseline, 3and 6-mo Follow-up of Part 1)
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During Part 2(From Treatment + 1 day up to Week 7 of Part 2)
研究者
研究点 (1)
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