- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04725812
Complement Regulation to Undo Systemic Harm in Preeclampsia (CRUSH)
Complement Regulation to Undo Systemic Harm in Preeclampsia: The CRUSH Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The purpose of this study is to determine if eculizumab is an effective treatment to prolong pregnancy in women with preeclampsia, compared to a historical control group of women that received standard of care alone. Eligible subjects will be women with preeclampsia before 30 weeks gestation, who have been deemed suitable for prolongation of pregnancy.
The primary research procedure is administration of the study drug, eculizumab, by intravenous infusions weekly for four weeks, then every other week. Eculizumab is approved by the FDA for the treatment of women with atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria and is frequently used in pregnant women with these disorders. However, eculizumab is considered investigational in this study because it has not been approved by the FDA for use in patients with preeclampsia. Subject participation will last approximately 8-12 weeks on average, and the study drug will be continued until 48 hours after delivery in the treatment arm. All subjects will be followed at 2 weeks and 6 weeks after delivery to assess maternal and neonatal outcomes. A later visit may be required to complete the meningococcal vaccine schedule.
The investigators believe that eculizumab will prolong pregnancy in women with preeclampsia diagnosed before 30 weeks gestation with overactive complement. As there is no effective treatment for preeclampsia other than delivery currently, women with preeclampsia before 30 weeks gestation are managed using a "watch and wait" approach (i.e., expectant management). Due to the unpredictable nature of preeclampsia, expectant management places mother and child at significant risk until delivery occurs. Eculizumab may be an improvement over current standard of care as it provides a treatment option for patients who would otherwise be managed with expectant management alone. If the study aims are achieved, eculizumab will emerge as an effective treatment option for women with preeclampsia.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
Los Angeles, California, United States, 90048
- Cedars-Sinai Medical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion criteria:
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures & availability for study duration
- Biologically female, aged ≥13, body weight ≥40kg
Diagnosed with preeclampsia between 23-29+6/7 weeks gestation, by following criteria:
- Blood pressure ≥160 mmHg systolic or ≥110 mmHg diastolic OR
- Blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic and at least one of the following
i. Proteinuria (spot protein/creatinine ≥0.3mg/mg or 24Hr protein ≥300 mg) ii. Platelet count <100,000/μl iii. Aspartate or alanine transaminase >2x upper limit of normal iv. Creatinine >1.1 mg/dl or oliguria v. Pulmonary edema
- Ability to take intravenous medication and be willing to adhere to the eculizumab regimen
- Ability to receive meningococcal vaccine and be willing to adhere to antibiotic regimen
Exclusion Criteria:
An individual who meets any of the following criteria prior to enrollment will be excluded from participation in this study:
- Known allergic reactions eculizumab or meningococcal vaccine
- Febrile illness within prior 2 weeks
- Treatment with another investigational drug within previous 6 months
- Inpatient expectant management for preeclampsia >72 hours prior to enrollment
- Fetal contraindication to expectant management of pregnancy
- Platelet count <50,000/μl
Diagnosis of hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome
- Must meet all of the following criteria to be excluded: LDH >600 U/L, platelet count < 100,000/μl, AST >2x upper limit of normal, ALT >2x upper limit of normal
- Diagnosis of Eclampsia
- Diagnosis of Placental abruption
- Intrauterine fetal demise
- Coagulopathy (INR ≥ 1.5)
- Fibrinogen <200 mg/dl
- Persistent, severe headache unresponsive to medications
- Persistent, severe visual disturbances
- Persistent, severe epigastric or RUQ pain unresponsive to medications
- Diagnosis of Systemic lupus erythematosus
- Diagnosis of Anti-phospholipid antibody syndrome
- Diagnosis of Atypical hemolytic uremic syndrome
- Diagnosis of Paroxysmal nocturnal hemoglobinuria
- Known complement deficiency
- Diagnosis of Venous thromboembolism active or within 6 months of enrollment
- Diagnosis of Human immunodeficiency virus (HIV)
- Diagnosis of Hepatitis C virus (active viremia)
- Diagnosis of Cancer (not in remission)
- History of Solid organ transplant
- Systemic viral or bacterial infection (active, untreated)
- Active use of eculizumab at time of enrollment
- Contraindication to eculizumab treatment or complement system blockade
- Contraindication to meningococcal vaccine
- Body weight <40kg
- Age <13
- Neutropenia (<1500/mm3)
- Gonorrhea, chlamydia, or syphilis in current pregnancy
- Illicit substance use in current pregnancy
- Currently homeless or incarcerated
- Alcoholism
- Liver cirrhosis
- Insulin dependent diabetes
- Active use of immunosuppressive therapies, other than use of corticosteroids for fetal lung maturity
- Use of prophylactic or therapeutic heparin, or low molecular weight heparin, in pregnancy for hypercoagulable condition
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Eculizumab
Twelve subjects in the interventional arm will receive eculizumab at an induction dose of 900mg IV weekly (q7 days) for 4 weeks followed by a dose of 1200mg IV at week 5.
Thereafter, patients will receive a maintenance dose of 1200mg IV every two weeks (q14 days).
The last dose of eculizumab will be given up to 48 hours post-partum, with a dose that is dependent on the dosing schedule (i.e.
whether the last dose is given within the 4-week induction period or is during the maintenance phase).
|
Eculizumab Intravenous Solution
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Latency (in Days) From Enrollment to Delivery
Time Frame: 24 months
|
The difference in mean number of days (latency) from enrollment in the study (or hospital admission for controls) to delivery between participant receiving eculizumab compared to historical controls.
|
24 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Composite Adverse Maternal Outcomes
Time Frame: 24 months
|
The difference in the composite number of adverse maternal outcomes between subjects receiving eculizumab compared to historical controls •Adverse maternal outcomes directly attributed to preeclampsia defined as the following: syndrome of hemolysis, elevated liver enzyme, and low platelet count (HELLP), eclampsia, placental abruption, stroke, venous thrombosis or pulmonary embolism, pulmonary edema, posterior reversible encephalopathy syndrome, postpartum hemorrhage (>1000 cc), blood transfusion, admission to the intensive care unit, acute kidney injury, acute tubular necrosis, dialysis, or death |
24 months
|
Composite Adverse Neonatal Outcomes
Time Frame: 24 months
|
The difference in the composite number of adverse neonatal outcomes between subjects receiving eculizumab compared to historical controls. •Adverse neonatal outcomes directly attributable to preeclampsia or indirectly attributable due to preterm delivery due to preeclampsia defined as the following: Respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, seizure, hypoxic-ischemic encephalopathy, metabolic acidosis, infection, sepsis, previously unrecognized major malformation detected at birth, patent ductus arteriosus requiring indomethacin, or death. |
24 months
|
Changes in Blood and Urine Concentrations of Terminal Complement Protein C5a Before and After Each Treatment.
Time Frame: 24 months
|
The Difference in the concentration of C5a in blood and urine, before treatment ( ex. visit day 1) compared to after treatment in each participant receiving eculizumab. •Concentrations of C5a in blood and urine will be determined by enzyme linked immunosorbent assays (ELISA). |
24 months
|
Changes in Blood and Urine Concentrations of Terminal Complement Protein C5b-9 Before and After Each Treatment.
Time Frame: 24 months
|
The difference in blood and urine concentrations of C5b-9, before treatment ( ex. visit day 1) compared to after treatment in each participant receiving eculizumab.
|
24 months
|
Changes in Blood and Urine Concentrations of Complement Protein CD59 Before and After Each Treatment.
Time Frame: 24 months
|
The difference in blood and urine concentrations of CD59, before treatment ( ex. visit day 1) compared to after treatment in each participant receiving eculizumab.
|
24 months
|
Aspartate and Alanine Transaminase Concentration Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentration of aspartate and alanine transaminase (U/L) will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Hemoglobin Concentration Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentrations of measures of hemoglobin will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Platelet Count Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the platelet count will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Lactate Dehydrogenase Concentration Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentration of serum lactate dehydrogenase will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Serum Creatinine Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentration of serum creatinine will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Urine Protein Concentration Before and After Each Treatment.
Time Frame: 24 months
|
Differences in urine protein concentration will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Ratio of Urine Protein to Urine Creatinine Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the ratio of urine protein concentration to urine creatinine concentration will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Serum Concentration of Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentration of soluble fms-like tyrosine kinase 1 (sFlt-1) will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Serum Concentration of Placental Growth Factor (PlGF) Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the concentration of placental growth factor (PlGF) will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Serum Ratio of Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Concentration to Placental Growth Factor (PlGF) Concentration (sFlt-1/PlGF) Before and After Each Treatment.
Time Frame: 24 months
|
Differences in the serum ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) concentration to placental growth factor (PlGF) concentration (sFlt-1/PlGF) will be compared before treatment (ex.
visit day 1) and after treatment in each participant receiving eculizumab.
|
24 months
|
Serious Adverse Events
Time Frame: 24 months
|
Assessment of serious adverse events in eculizumab treatment arm compared with historical controls.
|
24 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Richard Burwick, MD, MPH, Cedars-Sinai Medical Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Disease
- Pregnancy Complications
- Hypertension, Pregnancy-Induced
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Syndrome
- Pre-Eclampsia
- HELLP Syndrome
- Physiological Effects of Drugs
- Immunosuppressive Agents
- Immunologic Factors
- Complement Inactivating Agents
- Eculizumab
Other Study ID Numbers
- STUDY00000039
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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