Resistance to ErythroPoietin Effectiveness Algorithm Trial
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 7
- 主要终点
- Primary End-points:
研究概览
简要总结
A strategy for optimizing erythropoietin therapy in patients with erythropoietin resistance. A multi-centered, open-label, randomized, controlled trial.
详细描述
Study Rationale
Many treatable causes of erythropoietin resistance (also known as erythropoietin hypo-responsiveness) exist in patients with chronic kidney disease (CKD) stages 3 to 5 . Well recognized causes of erythropoietin resistance include iron deficiency, severe hyperparathyroidism, chronic infection, vitamin deficiency, aluminum toxicity and poor dialysis adequacy. Furthermore, many diseases resulting in the chronic inflammatory state have also been associated with erythropoietin resistance in Non-CKD patients with diseases such as chronic congestive heart failure, chronic liver disease and many connective tissue diseases including rheumatoid arthritis and systemic lupus.
It is now well recognized that CKD stage 5 patients receiving dialysis may also be at risk of developing chronic inflammation resulting in a more severe syndrome characterized by malnutrition and resistance to exogenous erythropoietin replacement therapy. Markers of a chronic inflammatory state that are observed in dialysis patients include hypoalbuminemia, elevated C-reactive protein (CRP), elevated ferritin, increased serum amyloid A and low transferrin saturation. In addition, pro-inflammatory cytokines such as interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) have been shown in vivo to suppress erythroid colony forming units. Erythrocyte lifespan can also be shortened through increased clearance by macrophages that are activated by inflammatory signals and immunoglobulin coated erythrocytes.
Inflammation also affects iron metabolism at many levels. Inflammatory cytokines can lead to reduced serum concentrations of iron and transferrin. Reduction in transferrin then leads to decreased iron absorption via the gut. Lactoferrin in polymorphonuclear cells can act as an iron scavenger with bactericidal activity. Lactoferrin levels have been shown to increase in inflammation and can bind large amounts of free iron, thereby reducing overall availability. Functional iron deficiency, which is also a characteristic the inflammatory state associated with erythropoietin resistance is defined as low availability of iron for erythropoiesis despite normal or high iron stores. Functional iron deficiency can occur in two ways; when high doses of exogenous erythropoietin stimulate erythropoiesis and it exceeds the capacity to deliver adequate iron or alternatively, when delivery of iron from the reticuloendothelial system to hematopoietic cells is blocked. Both mechanisms may occur in patients with chronic inflammation and erythropoietin resistance.
Erythropoietin resistance has been defined in several ways. In studies that analyzed Eprex® use, authors have utilized a dose cut off point of >200units of Eprex®/kg/week as a reasonable marker of 'true' erythropoietin resistance, or erythropoietin resistance occurring with no obvious cause contributing to a poor Eprex® response. Other authors have used the dose cut point of >300units /kg/week to define erythropoietin resistance. Furthermore, a measure of erythropoietin resistance called the Eprex® dose to hematocrit ratio (Eprex®/Hct) has been used as a continuous variable in some studies and has been shown to be positively correlated with certain markers of erythropoietin resistance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •written informed consent
- •Adult patients > 18 years old with current Epoetin Alpha dose >250 units/kg/wk
- •Hemoglobin >90g/L or <130g/L
- •Patients whom a temporary fall in Hb of up to 10g/L is deemed safe
- •Patients not expected to have a change in the type of Epo or route of Epo therapy for the duration of the Study period
排除标准
- •Known iron deficiency (% saturation <20 or ferritin <100)
- •Vit B12 or folate deficiency (levels below normal limit for centre lab)
- •Known malignancy (solid organ, leukemia or multiple myeloma)
- •Jehovah's witness patients/those who refuse transfusion
- •Expected to die in the next 6 months
- •On dialysis less than 3 months
- •Temporary (not tunneled) dialysis access catheter
- •Pure red cell aplasia
- •High likelihood of early withdrawal or interruption of the study (eg. severe or unstable coronary artery disease, stroke, severe liver disease within the 12 weeks before screening)
- •Planned major elective surgery during the study period
- •Pregnancy or breast-feeding
- •Women of child-bearing potential without effective contraception (abstinence, oral contraceptives, diaphragm, IUD)
- •Administration of another investigational drug within 4 weeks before screening or planned during study period
研究组 & 干预措施
Dosage Decrease Arm
Arm 2 is to have an decrease of erythropoietin at regular intervals.
干预措施: erythropoietin (Drug)
结局指标
主要结局
Primary End-points:
时间窗: December 31, 2009
Eprex® dose at the completion of the study period
时间窗: December 31, 2009
Hemoglobin at completion of the study period (average of last 2 Hb measurements)
时间窗: December 31, 2009
次要结局
- Number of transfusions of packed red cells(December 31, 2009)
- # of active infections during the study period (active infection is defined in Appendix B)(December 31, 2009)
- Hospitalization(December 31, 2009)
- Difference in HRQOL scores using Renal SF-36 scores taken at study start and completion study completion(December 31, 2009)
- Death(December 31, 2009)