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Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery (RAAPID-II)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01404910
Recruitment Status : Completed
First Posted : July 28, 2011
Last Update Posted : March 16, 2017
Kaneka Pharma America LLC
Information provided by (Responsible Party):
Ravi Thadhani, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE July 26, 2011
First Posted Date  ICMJE July 28, 2011
Last Update Posted Date March 16, 2017
Study Start Date  ICMJE May 2013
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2015)
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). [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 10, 2015)
  • Maternal and fetal safety [ Time Frame: 12 months ]
    Maternal: Blood pressure, proteinuria, coagulation parameters, elevated liver enzymes, and low platelet count (HELLP) syndrome, maternal complications Fetal: Early fetal assessments delivery (birth) will include gestational age, birth weight, length, fetal APGAR scores (1'/5'/10'), amniotic fluid volume by ultrasonography, and head circumference, NICU details, pulmonary parameters and any neonatal complications (eg, ventilatory support, respiratory distress syndrome, CRIB-Score, cerebral hemorrhage, ischemic colitis, and retinopathy of prematurity [ROP]) and compared to historical milestones. Fetal cord blood (with maternal consent) is to be sampled from umbilical artery at delivery to determine sFlt-1 levels, to measure pH and stored for later biochemical analyses. Fetal assessments will also occur ~30, 60, 90 and 365 days after delivery.
  • Maternal and fetal efficacy [ Time Frame: 12 months ]
    Maternal: Prolongation of pregnancy, reduction in blood pressure and proteinuria Fetal: Outcomes will be collected on all births, at birth, 24-hours post-partum, 72-hours post-partum, 30 day status vs historical milestones. 90 and 365 day assessments will be made using data obtained from medical records.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery
Official Title  ICMJE 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)
Brief Summary

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.

Detailed Description

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:

  1. 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
  2. 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).

UPDATE: The DSMB reviewed data after the first 4 patients and again after 10 patients/delivered infants had been treated. In the next 6 patients, DSMB review will occur after every 3 patients/delivered infants. These remaining 6 patients may undergo apheresis up to 3 times per week.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Preeclampsia
Intervention  ICMJE Device: Apheresis using Liposorber LA-15 System
The Liposorber LA-15 Device is a dextran sulfate cellulose column, one of several currently approved in Europe and United States for pheresis of lipoproteins in the treatment of familial hypercholesterolemia. Such devices have been in use for over 30 years. Published experience in pregnant women with familial hypercholesterolemia suggests that lipoprotein pheresis can be safely used in pregnancy after appropriate individual benefit/risk assessment for both mother and fetus is considered. The Liposorber LA-15 system selected for this trial has been evaluated for its ability to efficiently and selectively remove sFlt-1 in vitro.
Study Arms  ICMJE Experimental: Apheresis
Apheresis using Liposorber LA-15 System
Intervention: Device: Apheresis using Liposorber LA-15 System
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 25, 2015)
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria (maternal):

  1. Signed informed consent in a pregnant woman ages 18 and 45 years hospitalized for pre-term preeclampsia
  2. 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 >0.30.
  3. sFlt-1/PlGF ratio >85 (blood levels of sFlt-1 and PlGF determined using CE-approved Roche Diagnostics assays).

Exclusion Criteria (Maternal and Fetal):


  1. Taking any form of angiotensin cascade blocker
  2. History or diagnosis of pre-existing chronic hypertension (first 3 patients only)
  3. History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valvular disease
  4. History or diagnosis of chronic renal disease
  5. Patients receiving anticoagulation therapy prior to study entry
  6. Anticipated immediate delivery within 24 hours
  7. Signs of central nervous system (CNS) dysfunction, including seizures, cerebral edema (CT-scan or MRI)
  8. History of thyroid disease
  9. History of liver abnormalities
  10. Pulmonary edema
  11. Thrombocytopenia (platelet count < 100,000/mm3)
  12. Anemia - hemoglobin < 8 g/dL
  13. Evidence of "reverse Doppler" flow on umbilical Doppler
  14. Placenta previa
  15. Placental abruption
  16. Pre-term labor
  17. Active hepatitis B, C, or tuberculosis infection or HIV positive status
  18. Any condition that the investigator deems a risk to the patient or fetus in completing the study.
  19. 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:

  1. Trisomy
  2. Biophysical profile (BPP) < 6
  3. Amniotic fluid index (AFI) < 5 cm
  4. Estimated fetal weight (EFW) < 5th percentile for gestational age (IUGR)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01404910
Other Study ID Numbers  ICMJE 2012-P-000467/1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ravi Thadhani, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Kaneka Pharma America LLC
Investigators  ICMJE
Principal Investigator: Ravi I Thadhani, MD, MPH Massachusetts General Hospital
Principal Investigator: Thomas Benzing, MD University of Koln
Principal Investigator: Holger Stepan, MD University of Leipzig
PRS Account Massachusetts General Hospital
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP