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

Primary Purpose

Preeclampsia

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Apheresis using Liposorber LA-15 System
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Preeclampsia focused on measuring Pregnancy, Preeclampsia, Pre-term, sFlt-1, Apheresis, Hypertension, Proteinuria, VEGF

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

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):

Maternal:

  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)

Sites / Locations

  • Massachusetts General Hospital
  • University Hospital of Cologne (Universitat zu Koln)
  • University Hospital Leipzig

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Apheresis

Arm Description

Apheresis using Liposorber LA-15 System

Outcomes

Primary Outcome Measures

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).
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.

Secondary Outcome Measures

Maternal and fetal safety
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
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.

Full Information

First Posted
July 26, 2011
Last Updated
March 14, 2017
Sponsor
Massachusetts General Hospital
Collaborators
Kaneka Medical America LLC
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1. Study Identification

Unique Protocol Identification Number
NCT01404910
Brief Title
Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery
Acronym
RAAPID-II
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Completed
Study Start Date
May 2013 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Kaneka Medical America LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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: 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). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Preeclampsia
Keywords
Pregnancy, Preeclampsia, Pre-term, sFlt-1, Apheresis, Hypertension, Proteinuria, VEGF

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Apheresis
Arm Type
Experimental
Arm Description
Apheresis using Liposorber LA-15 System
Intervention Type
Device
Intervention Name(s)
Apheresis using Liposorber LA-15 System
Intervention Description
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.
Primary Outcome Measure Information:
Title
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).
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Maternal and fetal safety
Description
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.
Time Frame
12 months
Title
Maternal and fetal efficacy
Description
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.
Time Frame
12 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (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 >0.30. sFlt-1/PlGF ratio >85 (blood levels of sFlt-1 and PlGF determined using CE-approved Roche Diagnostics assays). Exclusion Criteria (Maternal and Fetal): Maternal: 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: Trisomy Biophysical profile (BPP) < 6 Amniotic fluid index (AFI) < 5 cm Estimated fetal weight (EFW) < 5th percentile for gestational age (IUGR)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ravi I Thadhani, MD, MPH
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Thomas Benzing, MD
Organizational Affiliation
University of Koln
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Holger Stepan, MD
Organizational Affiliation
University of Leipzig
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02116
Country
United States
Facility Name
University Hospital of Cologne (Universitat zu Koln)
City
Köln
ZIP/Postal Code
50923
Country
Germany
Facility Name
University Hospital Leipzig
City
Leipzig
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21810665
Citation
Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC, Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA, Benzing T. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011 Aug 23;124(8):940-50. doi: 10.1161/CIRCULATIONAHA.111.034793. Epub 2011 Aug 1.
Results Reference
background
PubMed Identifier
26405110
Citation
Easterling TR. Apheresis to Treat Preeclampsia: Insights, Opportunities and Challenges. J Am Soc Nephrol. 2016 Mar;27(3):663-5. doi: 10.1681/ASN.2015070794. Epub 2015 Sep 24. No abstract available.
Results Reference
background
PubMed Identifier
26405111
Citation
Thadhani R, Hagmann H, Schaarschmidt W, Roth B, Cingoez T, Karumanchi SA, Wenger J, Lucchesi KJ, Tamez H, Lindner T, Fridman A, Thome U, Kribs A, Danner M, Hamacher S, Mallmann P, Stepan H, Benzing T. Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. J Am Soc Nephrol. 2016 Mar;27(3):903-13. doi: 10.1681/ASN.2015020157. Epub 2015 Sep 24.
Results Reference
result

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Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery

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