Clinical trial NCT01404910: Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery
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
Overall status: COMPLETED
Phase: NA
Conditions: Preeclampsia
Keywords: Pregnancy
Preeclampsia
Pre-term
sFlt-1
Apheresis
Hypertension
Proteinuria
VEGF
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Kaneka Medical America LLC
First posted: 2011-07-28
Enrollment: 11
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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).
timeFrame: 12 months
Secondary outcomes:
measure: Maternal and fetal safety
timeFrame: 12 months
measure: Maternal and fetal efficacy
timeFrame: 12 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Köln
country: Germany
facility: University Hospital of Cologne (Universitat zu Koln)
city: Leipzig
country: Germany
facility: University Hospital Leipzig
Study officials:
affiliation: Massachusetts General Hospital
name: Ravi I Thadhani, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Koln
name: Thomas Benzing, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Leipzig
name: Holger Stepan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.