Usefulness of Extracorporeal Removal of sFLT-1 in Women With Very Early Severe Preeclampsia

Study Overview
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Brief Summary
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Introduction Preeclampsia is a multifactorial disease that is responsible of important adverse maternal and perinatal outcomes. Recently, it has been suggested that soluble fms-like tyrosine kinase 1, s-Flt1, induces preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. The aim of our study is to see whether removal of s-Flt1 may improve perinatal death in women with very early severe preeclampsia at less than 26 weeks' gestation Patients and methods Phase II trial. Women with singleton pregnancy having severe preeclampsia at 23-256/7 weeks' gestation. Women under 18 years, with multiples, or severe fetal growth restriction (less than 5th centile), or abnormal fetal heart rate, or maternal complications (abruption, eclampsia, HELLP syndrome, pulmonary edema, DIC, liver hematoma) are excluded from the study. After blood pressure and maternal stabilization, women are approached for information and if they agree, to sign the trial consent. Women have twice weekly extracorporeal removal of s-Flt1 until 34 weeks' gestation. Primary endpoint or success of the procedure: baby alive or alive at 6 months if hospitalized Statistical procedure Simon minimax plan; P0: 60%, P1, 90%, alpha error: 5%, beta power; 90%. First step: number 8 patients. If success equal or less than 5, the study is stopped. Second step: if success of 6 or more, the study is continued for 9 more patients. Overall, a maximum of 17 patients will be included. The final success of extracorporeal removal of s-Flt1 will be considered if 14 or more babies will be alive or alive at 6 months if hospitalized.

Detailed Description
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Introduction Preeclampsia is a multifactorial disease that is responsible of important adverse maternal and perinatal outcomes. Recently, it has been suggested that soluble fms-like tyrosine kinase 1, s-Flt1, induces preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. The aim of our study is to see whether removal of s-Flt1 may improve perinatal death in women with very early severe preeclampsia at less than 26 weeks' gestation Patients and methods Phase II trial. Women with singleton pregnancy having severe preeclampsia at 23-256/7 weeks' gestation. Women under 18 years, with multiples, or severe fetal growth restriction (less than 5th centile), or abnormal fetal heart rate, or maternal complications (abruption, eclampsia, HELLP syndrome, pulmonary edema, DIC, liver hematoma) are excluded from the study. After blood pressure and maternal stabilization, women are approached for information and if they agree, to sign the trial consent. They will then be admitted to the department of Renal intensive care of Tenon Hospital. LDL apheresis will be performed twice weekly, during 90 minutes per session, using the DALI 750 Kit and the ART device (Fresenius). sFlt1 will be measured in peripheral blood before and after each session. The treatment will end when delivery is indicated (whether because of threatening complications or because a viable term of pregnancy is achieved). Primary endpoint or success of the procedure: a live born baby alive at 6 month after birth. Secondary endpoints: days of pregnancy prolongation, blood pressure during apheresis, fetal heart rate monitoring after apheresis, maternal levels of s-Flt1, PlGF, and s-endoglin. Maternal adverse outcomes: eclampsia, HELLP syndrome, DIC, pulmonary edema, abruption placentae, renal failure. Neonatal outcome: gestational age at delivery, birth weight, Apgar score, patent ductus arteriosus, RDS, PVL, IVH, NEC, days in NICU. Statistical procedure Simon minimax plan; P0: 60%, P1, 90%, alpha error: 5%, beta power; 90%. First step: number 8 patients. If success equal or less than 5, the study is stopped. Second step: if success of 6 or more, the study is continued for 9 more patients. Overall, a maximum of 17 patients will be included. The final success of extracorporeal removal of s-Flt1 will be considered if 14 or more babies will be alive at 6 months after birth

Official Title
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Usefulness of Extracorporeal Removal of sFlt-1 in Women With Severe Preeclampsia at Less Than 26 Weeks' Gestation

Conditions
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Preeclampsia

Intervention / Treatment
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* Device: Apheresis for extracorporal removal of sFlt-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe preeclampsia at less than 26 weeks' gestation Singleton pregnancy Signed consent Exclusion Criteria: Multiple pregnancy Gestational age at 26 or above weeks' gestation Estimated foetal weight at diagnosis <5th percentile Abnormal fetal heart rate at entry, where feasible (>24 weeks' gestation) Maternal complications at diagnosis: Uncontrolled blood pressure, HELLP syndrome, abruption, eclampsia pulmonary edema, renal failure, liver hematoma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apheresis arm<br>Apheresis for extracorporal removal of sFlt-1 | Device: Apheresis for extracorporal removal of sFlt-1<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baby discharged alive or alive at 6 months if hospitalized | During the first step (inclusion of 8 patients) analysis is done continuously, and if 3 women have unsuccess primary endpoint, first step and the study are stopped, with a conclusion of failure of the procedure of lipapheresis. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy prolongation and preeclampsia related adverse outcomes | The data will be measured during the participation of the patient : 15 weeks = 11 weeks of pregnancy monitoring (from 23 to 34 weeks' gestation) + 4 weeks postpartum | 15 weeks | 
| Immunoadsorption tolerance for the mother during the session of lipapheresis | A description of the following variables will be used: blood pressure during the session, infectious or hemorrhagic events subsequent infusion and / or technique. The time frame is 11 weeks as a maximum : 11 weeks of pregnancy monitoring (from 23 to 34 weeks' gestation) | 11 weeks | 
| Foetal immunoadsorption tolerance during the session of lipapheresis | Measuring of the heart monitoring's data will be used. The time frame is 11 weeks as a maximum : 11 weeks of pregnancy monitoring (from 23 to 34 weeks' gestation) | 11 weeks | 
| Circulating levels of sFlt1, the placental growth factor (PlGF) and soluble endoglin (sEng) until deliverance | For the measure of the maternal adsorptive efficiency, the following parameters will be described: circulating levels of sFlt1, the placental growth factor (PlGF) and soluble endoglin (sEng). The time frame is 12 weeks : 11 weeks of pregnancy monitoring (from 23 to 34 weeks' gestation) + until deliverance | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early severe preeclampsia, Angiogenic factor, Apheresis