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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Massachusetts General Hospital
Sponsor:
Collaborator:
Kaneka Pharma America Corporation
Information provided by (Responsible Party):
Ravi Thadhani, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01404910
First received: July 26, 2011
Last updated: June 24, 2013
Last verified: June 2013

July 26, 2011
June 24, 2013
June 2013
June 2014   (final data collection date for primary outcome measure)
Reduction of sFlt-1 levels in maternal blood (first week of pheresis) measured immediately before pheresis therapy and at 2, 4, 12, 24, 48, 72, 96, 120 and 144 hours following termination of the pheresis therapy. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
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.
Not Provided
Complete list of historical versions of study NCT01404910 on ClinicalTrials.gov Archive Site
  • Maternal and fetal safety [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

    Maternal:

    Blood pressure, proteinuria, coagulation parameters, elevated liver enzymes, and low platelet count (HELLP) syndrome, maternal complications

    Fetal:

    Early fetal assessments including neonatal intensive care unit (NICU) admission, fetal APGAR scores, cerebral hemorrhage, pulmonary parameters, respiratory distress (eg, requirement for ventilation support), ischemic colitis, and retinopathy will be recorded.

  • Maternal and fetal efficacy [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    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. Fetal parameters to be collected include biophysical profile, measurements of size and weight, pH of umbilical arterial blood, APGAR scores (1'/5'/10'), body weight and length, head circumference and physical examination, selected laboratory values.

Not Provided
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Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery
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)

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 adsorption pheresis with the LIPOSORBER LA-15 System will be the primary intervention using methods that have been previously applied in pregnant women with familial hypercholesterolemia.

The primary objective of this trial is to determine whether short-term pheresis 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 pheresis 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 12 patients will be enrolled. Initially, 3 patients will undergo pheresis 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, the first 3 patients will be offered the option to continue pheresis 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 9 additional patients will be enrolled, with DSMB review after every 3 patients/delivered infants, and undergo pheresis with the Device in a similar or modified schedule (up to 3 times per week) to be based on data collected in the first 3 patients.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Preeclampsia
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.
Experimental: Apheresis
Apheresis using Liposorber LA-15 System
Intervention: Device: Apheresis using Liposorber LA-15 System
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
12
June 2014
June 2014   (final data collection date for primary outcome measure)

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)
Female
18 Years to 45 Years
No
Contact: Ravi I Thadhani, MD, MPH 617-724-1207 rthadhani@partners.org
United States,   Germany
 
NCT01404910
2012-P-000467/1
Yes
Ravi Thadhani, Massachusetts General Hospital
Massachusetts General Hospital
Kaneka Pharma America Corporation
Principal Investigator: Ravi I Thadhani, MD, MPH Massachusetts General Hospital
Principal Investigator: Thomas Benzing, MD University of Koln
Principal Investigator: Holger Stepan, MD University Hospital Leipzig
Massachusetts General Hospital
June 2013

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