Proof-of-Concept Trial on Selective Removal of sFlt-1 in Pregnant Women With Preeclampsia Via Apheresis

Study Overview
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Brief Summary
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This clinical investigation is a medical device trial to examine the safety and efficacy of TheraSorb sFlt-1 adsorber treatment of pregnant patients with preeclampsia.

Official Title
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Proof-of-Concept Trial on Selective Removal of the Antiangiogenic Factor Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) in Pregnant Women With Preeclampsia Via Apheresis Utilizing the Flt-1 Adsorption Column

Conditions
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Preeclampsia

Intervention / Treatment
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* Device: TheraSorb sFlt-1 adsorber


Participation Criteria
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Eligibility Criteria
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Reduced criteria! Phase 0 Inclusion Criteria: Age ≥18 and ≤45 years; Male or female; Female subjects of childbearing potential must have a negative serum pregnancy test result at screening and practice two reliable methods of contraception throughout the study. Exclusion Criteria: Dysfunction of cerebral nervous system and/or heart disease; History of preexisting chronic renal disease; Treatment with ACE inhibitors; Therapeutic full anticoagulation therapy prior to trial entry; Liver abnormalities; Clinically significant pulmonary edema and/or thrombocytopenia and/or anemia; Active hepatitis B, C, or tuberculosis infection or HIV infection Hypersensitivity to heparin and/or citrate; Indications that prohibit transient anticoagulation using heparin and/or ACD-A-solutions; Known intolerance to extracorporeal procedures in general or towards one of the individual excipients or towards other supporting agents; Drug or alcohol abuse within the last 2 years; Lack of compliance of subject; History or diagnosis of severe periodontitis; Phase A and B Inclusion Criteria: Age >18 and ≤45 years ; Pregnant woman with pre-term preeclampsia sFlt-1/PlGF ratio ≥85 ; sFlt-1 level of ≥ 8000pg/mL Exclusion Criteria: Maternal exclusion criteria History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valve disease; History of preexisting chronic renal disease (CKD stage >3a, eGFR ≤45ml/min/1.73m²); Treatment with ACE inhibitors; Therapeutic full anticoagulation therapy prior to trial entry; Signs or history of clinically significant cerebral nervous system dysfunction; History of clinically significant liver abnormalities; Clinically significant pulmonary edema and/or thrombocytopenia and/or anemia; Active hepatitis B, C, tuberculosis infection or HIV-positive status; Any condition that the investigator deems a risk to the patient or fetus in completing the trial; Indications that prohibit transient anticoagulation using heparin and/or ACD-A-solutions; Drug or alcohol abuse within the last 2 years; Lack of compliance of patient; Known intolerance to extracorporeal procedures in general or to one of the excipients or other supporting agents; Hypersensitivity to heparin and/or citrate; < 30 0/7 weeks of gestation and abnormal CTG and/or abnormal Ductus venosus Doppler flow, ≥30 0/7 weeks of gestation and Doppler evidence of umbilical artery Absent or Reversed End-Diastolic Velocity (AREDV); Various Placental exclusion criteria; Multiple pregnancy History or diagnosis of severe periodontitis Fetal exclusion criteria Any known trisomy; Amniotic fluid index <5cm (greatest single pocket <2cm); Estimated fetal weight <3rd percentile for gestational age; Fetus which are at high risk of heart disease; Fetus with congenital heart defect; Fetal signs of bleeding; Hydrops fetalis; Pathological fetal Doppler flow of the ductus venosus (absent A-wave in two measurements); Evidence of severe fetal malformations; Known infection of fetus; Known severe anemia.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 0 - healthy volunteers<br>Phase 0 is an initial safety phase where subjects will undergo one single TheraSorb sFlt-1 adsorber apheresis procedure. | Device: TheraSorb sFlt-1 adsorber<br>* Removal of excessive sFlt-1 from the plasma of subjects/ patients with therapeutic apheresis.<br>|
| Experimental: Phase A - preeclampsia patients<br>Phase A is a safety and dose-finding phase during which pregnant women diagnosed with preeclampsia will undergo one single TheraSorb sFlt-1 adsorber apheresis procedure. | Device: TheraSorb sFlt-1 adsorber<br>* Removal of excessive sFlt-1 from the plasma of subjects/ patients with therapeutic apheresis.<br>|
| Experimental: Phase B - preeclampsia patients<br>Phase B is a safety and efficacy phase during which pregnant women diagnosed with preeclampsia will undergo TheraSorb sFlt-1 adsorber apheresis procedures up to twice weekly. | Device: TheraSorb sFlt-1 adsorber<br>* Removal of excessive sFlt-1 from the plasma of subjects/ patients with therapeutic apheresis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of AEs and SAEs in healthy volunteers until the 2 weeks follow-up (Phase 0) |  | until 2 weeks post treatment | 
| Occurrence of AEs and SAEs in pregnant subjects and the fetus or infant until the 6 weeks post-delivery visit is reached (Phase A-B). |  | until 6 weeks post delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0: Determine changes of sFlt-1 levels. |  | until 2 weeks post treatment | 
| Phase 0: Complement activation levels pre-, during and post apheresis. |  | Before, during and directly following the performance of the single apheresis treatment (1 day) | 
| Phase 0: Concentration of antibody leaching during an apheresis procedure |  | During an apheresis procedure (1 day) | 
| Phase 0: Change of HAMA levels in pre- and post apheresis blood |  | until 2 weeks post treatment | 
| Phase 0: Evaluate blood pressure values |  | until 2 weeks post treatment | 
| Phase 0: Evaluate spot urine values |  | until 2 weeks post treatment | 
| Phase A/B: Occurrence of SAEs in the one year follow-up period |  | until end of FU, (1 year) | 
| Phases A/B: Evaluate antibody leaching in phase A. |  | During the performance of the single apheresis treatment in Phase A (1 day) as well as pre and 3hrs post apheresis | 
| Phases A and B: Evaluate maternal sFlt-1 levels. |  | Constant measures throughout the trial until delivery (up to 19 weeks) | 
| Phases A/B: Evaluate the sFlt-1/PlGF ratio. |  | Constant measures throughout the trial until delivery (up to 19 weeks) | 
| Phases A/B:Evaluate neonatal umbilical cord blood sFlt-1 levels at birth. |  | at birth | 
| Phases A/B: Determine HAMA levels |  | until 6 week FU visit | 
| Phases A/B: Time and method of delivery, and anesthesia administered |  | at birth | 
| Phases A and B: Determine the post-partum maternal and neonatal length of hospitalization. |  | Following birth up to one year | 
| Phases A/B: Evaluate standard markers of fetal development throughout pregnancy. |  | From start of trial until delivery (up to 19 weeks) | 
| Phases A/B: Evaluate standard markers of neonatal development. |  | Directly following delivery until end of FU (1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apheresis, pregnancy, pre-eclampsia, PE, sFlt-1, Pre-term