PreeclampsiaRAAPID-IINCT01404910
Removal of Anti-Angiogenic Proteins in Preeclampsia Before Delivery
A study testing Apheresis using Liposorber LA-15 System in people with Preeclampsia, run by Massachusetts General Hospital at 3 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, women only
- Conditions the study is for
- Preeclampsia
- What is being tested?
- Apheresis using Liposorber LA-15 System
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 3 sitesin 2 countries
- Study dates
- May 2013to Sep 2015
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Signed informed consent in a pregnant woman ages 18 and 45 years hospitalized for pre-term preeclampsia
- 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.
- sFlt-1/PlGF ratio >85 (blood levels of sFlt-1 and PlGF determined using CE-approved Roche Diagnostics assays).
Who cannot join
- Maternal:
- Taking any form of angiotensin cascade blocker
- History or diagnosis of pre-existing chronic hypertension (first 3 patients only)
- History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valvular disease
- History or diagnosis of chronic renal disease
- Patients receiving anticoagulation therapy prior to study entry
Show all 25Show fewer
- Anticipated immediate delivery within 24 hours
- Signs of central nervous system (CNS) dysfunction, including seizures, cerebral edema (CT-scan or MRI)
- History of thyroid disease
- History of liver abnormalities
- Pulmonary edema
- Thrombocytopenia (platelet count < 100,000/mm3)
- Anemia - hemoglobin < 8 g/dL
- Evidence of "reverse Doppler" flow on umbilical Doppler
- Placenta previa
- Placental abruption
- Pre-term labor
- Active hepatitis B, C, or tuberculosis infection or HIV positive status
- Any condition that the investigator deems a risk to the patient or fetus in completing the study.
- 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:
- Trisomy
- Biophysical profile (BPP) < 6
- Amniotic fluid index (AFI) < 5 cm
- Estimated fetal weight (EFW) < 5th percentile for gestational age (IUGR)
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Germany2 sites
University Hospital of Cologne (Universitat zu Koln)
Cologne, 50923
University Hospital Leipzig
Leipzig
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02116
About this study
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)
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.
Read the 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:
- 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
- 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.
- Conditions
- Preeclampsia
- Being tested
- Apheresis using Liposorber LA-15 System
- Keywords
- Pregnancy, Preeclampsia, Pre-term, sFlt-1, Apheresis, Hypertension, Proteinuria, VEGF
- Medical subject headings
- Pre-Eclampsia, Premature Birth, Hypertension, Proteinuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Apheresis using Liposorber LA-15 SystemDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Apheresis | Experimental | Apheresis using Liposorber LA-15 System Receives: Device: Apheresis using Liposorber LA-15 System |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
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.
Measured: 12 months
Secondary outcomes (2)
Maternal and fetal safety
Maternal: Blood pressure, proteinuria, coagulation parameters, elevated liver enzymes, and low platelet count (HELLP) syndrome, maternal complications Fetal: Early fetal assessments delivery (birth) will include gestational age, birth weight, length, fetal APGAR scores (1'/5'/10'), amniotic fluid volume by ultrasonography, and head circumference, NICU details, pulmonary parameters and any neonatal complications (eg, ventilatory support, respiratory distress syndrome, CRIB-Score, cerebral hemorrhage, ischemic colitis, and retinopathy of prematurity [ROP]) and compared to historical milestones. Fetal cord blood (with maternal consent) is to be sampled from umbilical artery at delivery to determine sFlt-1 levels, to measure pH and stored for later biochemical analyses. Fetal assessments will also occur ~30, 60, 90 and 365 days after delivery.
Measured: 12 months
Maternal and fetal efficacy
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.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2011 (estimated)
- Study startMay 2013
- Primary completionSep 2015
- Study completionSep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for PreeclampsiaStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Kaneka Medical America LLC
- Responsible party
- Principal investigator, Ravi Thadhani, Massachusetts General Hospital
- Investigators
- Ravi I Thadhani, MD, MPH, Principal investigator, Massachusetts General HospitalThomas Benzing, MD, Principal investigator, University of KolnHolger Stepan, MD, Principal investigator, University of Leipzig
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01404910
- Sponsor's protocol ID
- 2012-P-000467/1
- Acronym
- RAAPID-II
- Status last verified
- Mar 2017
- First submitted
- 26 Jul 2011
- Last updated
- 16 Mar 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 21810665Easterling 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.
PubMed 26405110Thadhani 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.
PubMed 26405111
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT01404910
- Acronym / sponsor ID
- RAAPID-II / 2012-P-000467/1
- Conditions
- Preeclampsia
- Keywords
- Pregnancy, Preeclampsia, Pre-term, sFlt-1, Apheresis, Hypertension, Proteinuria, VEGF
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- Kaneka Medical America LLC
- Study start
- May 2013
- Primary completion
- Sep 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 28 Jul 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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
- 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Apheresis | Experimental | Device: Apheresis using Liposorber LA-15 SystemApheresis using Liposorber LA-15 System |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Signed informed consent in a pregnant woman ages 18 and 45 years hospitalized for pre-term preeclampsia
- 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.
- sFlt-1/PlGF ratio >85 (blood levels of sFlt-1 and PlGF determined using CE-approved Roche Diagnostics assays).
Key exclusion criteria (25 listed)
- Taking any form of angiotensin cascade blocker
- History or diagnosis of pre-existing chronic hypertension (first 3 patients only)
- History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valvular disease
- History or diagnosis of chronic renal disease
- Patients receiving anticoagulation therapy prior to study entry
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Apheresis using Liposorber LA-15 SystemThe 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. | Device | Apheresis |
Primary outcome
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).
Time frame: 12 months
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.
2 secondary outcomes
Maternal and fetal safety
Time frame: 12 months
Maternal and fetal efficacy
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2017.
- Background: PubMed 21810665Thadhani 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.
- Background: PubMed 26405110Easterling 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.
- Results publication: PubMed 26405111Thadhani 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.
- Individual participant dataSharing planned: No
Related trials for Preeclampsia
Recruiting
Exercise to Improve Heart and Metabolic Health After Childbirth in Women at High Risk for Preeclampsia
Postpartum Exercise, Cardiometabolic Health
RecruitingObservational study
Molecular Study of the Maternal-fetal Interface in Preeclampsia.
Preeclampsia
Active, not recruitingObservational study
The CoPenHagen PREeClampsia and cardIOvascUlar diSease Study
Pre-Eclampsia, Atherosclerosis
RecruitingObservational study
Estimated Risk of Preeclampsia in the First Trimester and Its Association With Subclinical Atherosclerosis and Cardiovascular Risk in Women With Type 1 Diabetes
Type 1 Diabetes, Preeclampsia
Not yet recruitingPhase 2
Furosemide vs Placebo in Severe Preeclampsia Postpartum
Severe Preeclampsia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ravi I Thadhani, MD, MPH principal investigator
Massachusetts General Hospital
Thomas Benzing, MD principal investigator
University of Koln
Holger Stepan, MD principal investigator
University of Leipzig
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Apheresis using Liposorber LA-15 System in people with Preeclampsia, run by Massachusetts General Hospital at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01404910, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2017.