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

• ClinicalTrials.gov Identifier: NCT02923206
• Recruitment Status: Recruiting
• First Posted: October 4, 2016
• Last Update Posted: January 18, 2020
• Sponsor: Miltenyi Biotec B.V. & Co. KG
• Collaborator: Cromsource
• Information provided by (Responsible Party): Miltenyi Biomedicine GmbH ( Miltenyi Biotec B.V. & Co. KG )

Tracking Information

• First Submitted Date: September 19, 2016
• First Posted Date: October 4, 2016
• Last Update Posted Date: January 18, 2020
• Actual Study Start Date: September 2016
• Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 3, 2016)

• Occurrence of AEs and SAEs in healthy volunteers until the 2 weeks follow-up (Phase 0) [ Time Frame: 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). [ Time Frame: until 6 weeks post delivery ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 23, 2017)

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

Original Secondary Outcome Measures (submitted: October 3, 2016)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Proof-of-Concept Trial on Selective Removal of sFlt-1 in Pregnant Women With Preeclampsia Via Apheresis
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Preeclampsia

Intervention

Device: TheraSorb sFlt-1 adsorber

Removal of excessive sFlt-1 from the plasma of subjects/ patients with therapeutic apheresis.

Study Arms

• Experimental: Phase 0 - healthy volunteers
  Phase 0 is an initial safety phase where subjects will undergo one single TheraSorb sFlt-1 adsorber apheresis procedure.
  Intervention: Device: TheraSorb sFlt-1 adsorber
• Experimental: Phase A - preeclampsia patients
  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.
  Intervention: Device: TheraSorb sFlt-1 adsorber
• Experimental: Phase B - preeclampsia patients
  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.
  Intervention: Device: TheraSorb sFlt-1 adsorber

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 3, 2016): 23
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 2022
• Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Thomas F Hiemstra, MD; +44 (0) 1223 336 817; tfh24@cam.ac.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT02923206
• Other Study ID Numbers: M-2016-313
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Miltenyi Biomedicine GmbH ( Miltenyi Biotec B.V. & Co. KG )
• Study Sponsor: Miltenyi Biotec B.V. & Co. KG
• Collaborators: Cromsource

Investigators

• Principal Investigator: Thomas F Hiemstra, MD; Cambridge Clinical Trials Unit Addenbrooke's Hospital

• PRS Account: Miltenyi Biomedicine GmbH
• Verification Date: January 2020