Phase 1b Proof-of-Concept Study of Apheresis to Reduce Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) in Pregnant Women With Preeclampsia Using a Dextran Sulfate Adsorption (DSA) Column (LIPOSORBER® LA-15 System)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 3
- 主要终点
- sFlt-1 levels measured immediately prior to each apheresis treatment, and at 2-4, 12, 24, etc. (every 24 hours) following termination of apheresis to determine kinetics of sFlt-1 clearance (until delivery).
研究概览
简要总结
Preeclampsia is a syndrome that occurs in approximately 3% to 8% of pregnancies and is associated with considerable maternal and neonatal morbidity and mortality. Except for termination of the pregnancy, effective treatments/preventative measures for preeclampsia are lacking. Although prolongation of pregnancy benefits the fetus, it is detrimental to the mother, and is associated with hypertension, proteinuria, and symptoms that suggest kidney, brain, liver and cardiovascular system involvement.
Placental soluble fms-like tyrosine kinase 1 (sFlt-1) is elevated in women with preeclampsia, with levels that fall after delivery. sFlt-1 is a variant of the vascular endothelial growth factor (VEGF) receptor Flt-1, and in the circulation, acts as a potent VEGF and placental growth factor (PlGF) antagonist. Given that sFlt-1 levels are elevated in preeclampsia, we are investigating if removal of sFlt-1 from the plasma of women with preeclampsia can improve maternal and fetal outcomes.
Short-term extracorporeal apheresis with the LIPOSORBER LA-15 System will be the primary intervention using methods that have been previously applied in pregnant women with familial hypercholesterolemia.
详细描述
The primary objective of this trial is to determine whether short-term apheresis using a dextran sulfate adsorption (DSA) column (Liposorber LA-15 System; the Device) leads to a reduction in circulating sFLT-1 in the blood of women with pre-term preeclampsia.
The following secondary objectives are aimed at evaluating the efficacy and safety of the Device as well as the impact of removing circulating sFlt-1 on maternal and neonatal outcomes:
- To determine whether short-term apheresis using the Device in women with pre-term preeclampsia leads to:
- a prolongation of pregnancy (ie, gestational age)
- a reduction in blood pressure (BP) and proteinuria
- an increase in fetal birth weight
- To determine the safety of reducing maternal sFlt-1 levels using the Device.
Up to 16 patients will be enrolled. Initially, 4 patients will undergo apheresis UP TO 2 times in the first week and undergo all protocol-related assessments including PK of sFlt-1 levels. Based on an assessment of clinical response by the Investigator, these first 4 patients will be offered the option to continue apheresis treatments (without pharmacokinetic [PK] assessments) up to twice weekly until delivery or until 34 weeks gestation, whichever comes first. Following complete review of all parameters and outcomes by an independent Data Safety Monitoring Board (DSMB), up to 12 additional patients will be enrolled (total of up to 16).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •(maternal):
- •Signed informed consent in a pregnant woman ages 18 and 45 years hospitalized for pre-term preeclampsia
- •Pre-term preeclampsia defined by systolic BP ≥140 mm Hg or ≥90 mm Hg diastolic at or after 23 weeks of gestation or at or before 32 weeks in gestation in a woman with previously normal BP and proteinuria 0.3 grams in a 24-hour specimen or urine protein/creatinine ratio >0.
- •sFlt-1/PlGF ratio >85 (blood levels of sFlt-1 and PlGF determined using CE-approved Roche Diagnostics assays).
排除标准
- •(Maternal and Fetal):
- •Taking any form of angiotensin cascade blocker
- •History or diagnosis of pre-existing chronic hypertension (first 3 patients only)
- •History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valvular disease
- •History or diagnosis of chronic renal disease
- •Patients receiving anticoagulation therapy prior to study entry
- •Anticipated immediate delivery within 24 hours
- •Signs of central nervous system (CNS) dysfunction, including seizures, cerebral edema (CT-scan or MRI)
- •History of thyroid disease
- •History of liver abnormalities
- •Pulmonary edema
- •Thrombocytopenia (platelet count < 100,000/mm3)
- •Anemia - hemoglobin < 8 g/dL
- •Evidence of "reverse Doppler" flow on umbilical Doppler
- •Placenta previa
- •Placental abruption
- •Pre-term labor
- •Active hepatitis B, C, or tuberculosis infection or HIV positive status
- •Any condition that the investigator deems a risk to the patient or fetus in completing the study.
- •Any condition which in the opinion of the investigator would necessitate delivery in the next 24 hours
- •Fetal characteristic that would exclude the mother from participating:
- •Biophysical profile (BPP) < 6
- •Amniotic fluid index (AFI) < 5 cm
- •Estimated fetal weight (EFW) < 5th percentile for gestational age (IUGR)
研究组 & 干预措施
Apheresis
Apheresis using Liposorber LA-15 System
干预措施: Apheresis using Liposorber LA-15 System (Device)
结局指标
主要结局
sFlt-1 levels measured immediately prior to each apheresis treatment, and at 2-4, 12, 24, etc. (every 24 hours) following termination of apheresis to determine kinetics of sFlt-1 clearance (until delivery).
时间窗: 12 months
The study period for each patient will be from initiation of the device until 30 days (± 7 days) after delivery. Additional assessments will be performed at 90 and 365 days (± 7 days, respectively) using maternal and neonatal medical records and/or by telephone contact with the mother.
次要结局
- Maternal and fetal safety(12 months)
- Maternal and fetal efficacy(12 months)
研究者
Ravi Thadhani
Director of Clinical Research in Nephrology
Massachusetts General Hospital