Clinical trial NCT04725812: Complement Regulation to Undo Systemic Harm in Preeclampsia
Official title: Complement Regulation to Undo Systemic Harm in Preeclampsia: The CRUSH Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Preeclampsia
Severe Preeclampsia
Eculizumab
HELLP
HELLP Syndrome
HELLP Syndrome Second Trimester
Pregnancy Related
AHUS
PNH
Complement Regulatory Factor Defect
Complement Abnormality
HELLP Syndrome Third Trimester
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Alexion Pharmaceuticals, Inc.
First posted: 2021-01-27
Enrollment: 2
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single arm open label study.
Primary purpose: TREATMENT

Brief summary: This is a Phase II, single arm, open-label study to determine if treatment with eculizumab prolongs pregnancy compared to historical controls in women with preeclampsia between 23-30 weeks gestation.

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.

Eligibility criteria: Inclusion criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures \& availability for study duration
3. Biologically female, aged ≥13, body weight ≥40kg
4. Diagnosed with preeclampsia between 23-29+6/7 weeks gestation, by following criteria:

   1. Blood pressure ≥160 mmHg systolic or ≥110 mmHg diastolic OR
   2. 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
5. Ability to take intravenous medication and be willing to adhere to the eculizumab regimen
6. 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:

1. Known allergic reactions eculizumab or meningococcal vaccine
2. Febrile illness within prior 2 weeks
3. Treatment with another investigational drug within previous 6 months
4. Inpatient expectant management for preeclampsia \>72 hours prior to enrollment
5. Fetal contraindication to expectant management of pregnancy
6. Platelet count \<50,000/μl
7. 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
8. Diagnosis of Eclampsia
9. Diagnosis of Placental abruption
10. Intrauterine fetal demise
11. Coagulopathy (INR ≥ 1.5)
12. Fibrinogen \<200 mg/dl
13. Persistent, severe headache unresponsive to medications
14. Persistent, severe visual disturbances
15. Persistent, severe epigastric or RUQ pain unresponsive to medications
16. Diagnosis of Systemic lupus erythematosus
17. Diagnosis of Anti-phospholipid antibody syndrome
18. Diagnosis of Atypical hemolytic uremic syndrome
19. Diagnosis of Paroxysmal nocturnal hemoglobinuria
20. Known complement deficiency
21. Diagnosis of Venous thromboembolism active or within 6 months of enrollment
22. Diagnosis of Human immunodeficiency virus (HIV)
23. Diagnosis of Hepatitis C virus (active viremia)
24. Diagnosis of Cancer (not in remission)
25. History of Solid organ transplant
26. Systemic viral or bacterial infection (active, untreated)
27. Active use of eculizumab at time of enrollment
28. Contraindication to eculizumab treatment or complement system blockade
29. Contraindication to meningococcal vaccine
30. Body weight \<40kg
31. Age \<13
32. Neutropenia (\<1500/mm3)
33. Gonorrhea, chlamydia, or syphilis in current pregnancy
34. Illicit substance use in current pregnancy
35. Currently homeless or incarcerated
36. Alcoholism
37. Liver cirrhosis
38. Insulin dependent diabetes
39. Active use of immunosuppressive therapies, other than use of corticosteroids for fetal lung maturity
40. Use of prophylactic or therapeutic heparin, or low molecular weight heparin, in pregnancy for hypercoagulable condition

Primary outcomes:
measure: Latency (in Days) From Enrollment to Delivery
timeFrame: 24 months
Secondary outcomes:
measure: Composite Adverse Maternal Outcomes
timeFrame: 24 months
measure: Composite Adverse Neonatal Outcomes
timeFrame: 24 months
measure: Changes in Blood and Urine Concentrations of Terminal Complement Protein C5a Before and After Each Treatment.
timeFrame: 24 months
measure: Changes in Blood and Urine Concentrations of Terminal Complement Protein C5b-9 Before and After Each Treatment.
timeFrame: 24 months
measure: Changes in Blood and Urine Concentrations of Complement Protein CD59 Before and After Each Treatment.
timeFrame: 24 months
measure: Aspartate and Alanine Transaminase Concentration Before and After Each Treatment.
timeFrame: 24 months
measure: Hemoglobin Concentration Before and After Each Treatment.
timeFrame: 24 months
measure: Platelet Count Before and After Each Treatment.
timeFrame: 24 months
measure: Lactate Dehydrogenase Concentration Before and After Each Treatment.
timeFrame: 24 months
measure: Serum Creatinine Before and After Each Treatment.
timeFrame: 24 months
measure: Urine Protein Concentration Before and After Each Treatment.
timeFrame: 24 months
measure: Ratio of Urine Protein to Urine Creatinine Before and After Each Treatment.
timeFrame: 24 months
measure: Serum Concentration of Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Before and After Each Treatment.
timeFrame: 24 months
measure: Serum Concentration of Placental Growth Factor (PlGF) Before and After Each Treatment.
timeFrame: 24 months
measure: 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.
timeFrame: 24 months
measure: Serious Adverse Events
timeFrame: 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Richard Burwick, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: