Efficacy and Safety of Thrombopoetin-Receptor Agonist Eltrombopag in in Combination With Ciclosporin A in Moderate Aplastic Anemia (EMAA): Prospective Randomized Multicenter Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 93
- 试验地点
- 1
- 主要终点
- Trilineage hematologic response rate (CR + PR)
研究概览
简要总结
The aim of this study is to improve treatment of Moderate Aplastic Anemia (MAA) by evaluating the safety and efficiency of Eltrombopag as a new treatment option in patients with therapy requiring MAA.
详细描述
After enrollment (see detailed inclusion and exclusion criteria below) the patients are randomized either to the Placebo or Eltrombopag arm. The randomization is double blinded. Randomization will take in account patient's age and disease severity by stratifying into 4 block combinations to ensure homogeneity between treatment arms. All patients receive background therapy with CSA, regardless of randomisation group, to treat MAA according to current standard of care.
Eltrombopag (or Placebo) is given at a daily starting dose of 150 mg orally as 75 mg tablets once daily (2 tablets Eltrombopag or placebo per day), (Olnes et al NEJM 2012).
In Asian patients Eltrombopag (or Placebo) is given at a daily starting dose of 75 mg orally (1 tablet Eltrombopag or placebo per day). In Asian-Caucasian patients no dose reduction of the starting dose is carried out, but cautious observation of the liver function due to the possibility of altered Eltrombopag metabolism is recommended.
Dose reduction:
In patients without history of thromboembolism or known risk factors for thrombembolism dose reduction (the possibility of an alternating dose schedule is given) is recommended if the platelet count is increasing > 150 G/L.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Current diagnosis of a Moderate Aplastic Anemia requiring standard treatment with CSA without prior specific therapy.
- •MAA is defined as Aplastic Anemia fulfilling the following criteria:
- •no evidence for other disease causing marrow failure
- •hypocellular bone marrow for age
- •depression of at least two out of three peripheral blood counts below the normal values:
- •absolute neutrophil count (ANC) < 1.2 G/L and > 0.5 G/l
- •platelet count < 70 G/L
- •absolute reticulocyte count < 60 G/L
- •without fulfilling the criteria for SAA (hypocellularity of bone marrow 25 % and depression of two of the three peripheral counts: ANC < 0.5 G/L, platelet count < 20 G/L, reticulocyte count < 20 G/L)
- •In this study need for treatment with CSA is defined as:
- •2a) transfusion-independent MAA and:
- •ANC < 1.0 G/L
- •or hemoglobin < 8.5 g/dl and reticulocyte count < 60 G/L
- •or platelet count < 30 G/L
- •or significant clinical symptoms (infections, bleeding, anemia)
- •2b) transfusion-dependent moderate aplastic anemia
- •Platelet transfusion dependency is defined as prophylactic transfusion (platelet counts < 10 G/L with no bleeding) or therapeutic transfusion in the 12 weeks prior to study entry
- •Red cell transfusion dependency is defined as transfusion of at least 4 units of packed red blood cell concentrates (PRBC) in the 12 weeks prior to study entry
- •A signed and dated informed consent is necessary before the conduct of any study-specific procedure.
排除标准
- •Age < 18 years
- •Severe or Very Severe Aplastic Anemia (hypocellularity of bone marrow 25 % and depression of two of the three peripheral counts: ANC < 0.5 G/L, platelet count < 20 G/L, reticulocyte count < 20 G/L)
- •Constitutional aplastic anemia (Fanconi anemia or Dyskeratosis congenita)
- •Clonal myeloid disorders based on cytogenetic findings performed within 12 weeks of study entry. Especially, patients with cytogenetic abnormalities which are recurrent in MDS are not eligible for the study.
- •Bone marrow reticulin fibrosis of grade 3 or greater
- •Severe concurrent diseases precluding the patient's ability to tolerate protocol therapy
- •ALT > 3 times the upper limit of normal if this elevation is progressive, or persistent for 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation
- •Infection not adequately responding to appropriate therapy
- •HIV-positivity (patients with Hepatitis B or Hepatits C-positivity are only in combination with hepatic failure (see criteria 7) excluded)
- •Moribund status with a likely death within 3 months
- •History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1, breast cancer in situ, cervical carcinoma in situ...).
- •Prior specific treatment of Aplastic Anemia with immunosuppression or androgens or interleukin2-receptor-antibodies. The use of these drugs in context of other disorders before diagnosis of aplastic anemia is not an exclusion criteria if these treatments were finished longer than 6 months before study entry.
- •Treatment with other hematological effective drugs (including erythropoetin) within 3 months before study entry as well as treatment with corticosteroids and G-CSF within 3 weeks before enrollment
- •Known hypersensitivity to Eltrombopag or its components
- •Known hypersensitivity to Ciclosporin
- •Current nursing, pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control to refrain from pregnancy as well as a missing or positive pregnancy test within the last 14 days before inclusion for women with childbearing potential during the course of this study.
- •Inability to understand the investigational nature of the study or to give informed consent.
- •Renal failure with creatinine > 2× upper limit of normal.
- •Uncontrolled hypertension
- •Participation in any study using an investigational drug or treatment with an investigational drug within 30 days preceding the first dose of study medication
研究组 & 干预措施
Eltrombopag + Ciclosporin A
Eltrombopag, 75 mg film tablets, starting dose: 2 tablets (150 mg per day), daily, per os
- According to European guidelines CSA is administered orally with an initial daily dose of 5 mg/kg/day divided into two doses. Then dosage should be adjusted with the aim of a trough CSA blood level of 200-400 ng/mL (using a polyclonal assay) or 150-250 ng/mL (using a monoclonal assay).
干预措施: Eltrombopag (Drug)
Placebo + Ciclosporin A
Placebo for Eltrombopag 75 mg film tablets, 2 tablets, daily, per os
- According to European guidelines CSA is administered orally with an initial daily dose of 5 mg/kg/day divided into two doses. Then dosage should be adjusted with the aim of a trough CSA blood level of 200-400 ng/mL (using a polyclonal assay) or 150-250 ng/mL (using a monoclonal assay).
干预措施: Placebo (for Eltrombopag) (Drug)
结局指标
主要结局
Trilineage hematologic response rate (CR + PR)
时间窗: 6 months after treatment start
The primary objective of this trial is to investigate whether Eltrombopag added to standard immunosuppressive treatment increases the rate of hematologic responses (complete and partial response) in untreated AA patient at six months after treatment start. A complete response (according to Marsh et al Blood 1992): A peripheral blood count with an ANC \> 2.0 G/L and a platelet count \> 100 G/L and transfusion independence. A partial response (according to Marsh et al Blood 1992): A peripheral blood count with an ANC \>1.0 G/L and a platelet count \>30 G/L and transfusion independence Transfusion independence is defined as No need for platelet transfusions in the last 4 weeks prior to evaluation and no need for packed red blood cell concentrates (PRBC) in the last 6 weeks prior to evaluation. Patients who remain transfusion-dependent will be classified as non-responders regardless of the ANC and platelet count.
次要结局
- cumulative incidence of response(3, 6, 12 and 18 months)
- Comparison of number of SAEs between the two arms (CSA + Placebo versus CSA + Eltrombopag(2 years)
- Trilineage hematological response rate (CR and PR, detailed definition => primary endpoint) at 3, 12 and 18(3, 12 and 18 months)
- single hematological response rate (CR and PR, detailed definition => primary endpoint) at 3, 12 and 18(3, 12 and 18 months)
研究者
B. Höchsmann
Dr. med.
University of Ulm