AHUS, Complement Abnormality, Complement Regulatory Factor Defect, Eculizumab, HELLP, HELLP Syndrome, HELLP Syndrome Second Trimester, HELLP Syndrome Third Trimester, PNH, Preeclampsia, Pregnancy Related, Severe Preeclampsia
Conditions
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.
Interventions
DRUGEculizumab
Eculizumab Intravenous Solution
Sponsors
Alexion Pharmaceuticals, Inc.
Cedars-Sinai Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm open label study.
Eligibility
Sex/Gender
FEMALE
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Latency (in Days) From Enrollment to Delivery | 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. * For treatment-arm participants latency is determined from enrollment to delivery. * For historical controls latency is determined from hospital admission (or initial diagnosis for controls hospitalized for other indication) for preeclampsia until delivery. * Subjects and historical controls all defined as women with preeclampsia between 23-30 weeks gestation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Adverse Neonatal Outcomes | 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. |
| Changes in Blood and Urine Concentrations of Terminal Complement Protein C5a Before and After Each Treatment. | 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). |
| Changes in Blood and Urine Concentrations of Terminal Complement Protein C5b-9 Before and After Each Treatment. | 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. |
| Changes in Blood and Urine Concentrations of Complement Protein CD59 Before and After Each Treatment. | 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. |
| Aspartate and Alanine Transaminase Concentration Before and After Each Treatment. | 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. |
| Hemoglobin Concentration Before and After Each Treatment. | 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. |
| Platelet Count Before and After Each Treatment. | 24 months | Differences in the platelet count will be compared before treatment (ex. visit day 1) and after treatment in each participant receiving eculizumab. |
| Composite Adverse Maternal Outcomes | 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 |
| Serum Creatinine Before and After Each Treatment. | 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. |
| Urine Protein Concentration Before and After Each Treatment. | 24 months | Differences in urine protein concentration will be compared before treatment (ex. visit day 1) and after treatment in each participant receiving eculizumab. |
| Ratio of Urine Protein to Urine Creatinine Before and After Each Treatment. | 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. |
| Serum Concentration of Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Before and After Each Treatment. | 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. |
| Serum Concentration of Placental Growth Factor (PlGF) Before and After Each Treatment. | 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. |
| 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. | 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. |
| Serious Adverse Events | 24 months | Assessment of serious adverse events in eculizumab treatment arm compared with historical controls. 1. Neisseria meningitidis infection or development of invasive meningococcal disease, Neisseria gonorrhoeae, Neisseria sicca/subflava, and Neisseria spp unspecified and Aspergillus infections. 2. Graded clinical and laboratory abnormalities, according to the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS; DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\]. |
| Lactate Dehydrogenase Concentration Before and After Each Treatment. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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: Eculizumab Intravenous Solution | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 37.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Latency (in Days) From Enrollment to Delivery
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. * For treatment-arm participants latency is determined from enrollment to delivery. * For historical controls latency is determined from hospital admission (or initial diagnosis for controls hospitalized for other indication) for preeclampsia until delivery. * Subjects and historical controls all defined as women with preeclampsia between 23-30 weeks gestation.
Time frame: 24 months
Population: 1 enrolled subject withdrew participation before delivery. A second subject withdrew consent after delivery.~Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects. Historical controls were not identified for this terminated study, thus this Outcome Measure cannot be reported.
Secondary
Aspartate and Alanine Transaminase Concentration Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Changes in Blood and Urine Concentrations of Complement Protein CD59 Before and After Each Treatment.
The difference in blood and urine concentrations of CD59, before treatment ( ex. visit day 1) compared to after treatment in each participant receiving eculizumab.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Changes in Blood and Urine Concentrations of Terminal Complement Protein C5a Before and After Each Treatment.
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).
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Changes in Blood and Urine Concentrations of Terminal Complement Protein C5b-9 Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Composite Adverse Maternal Outcomes
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
Time frame: 24 months
Population: 1 enrolled subject withdrew participation before delivery. A second subject withdrew consent after delivery.~Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects. Historical controls were not identified for this terminated study, thus this Outcome Measure cannot be reported.
Secondary
Composite Adverse Neonatal Outcomes
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.
Time frame: 24 months
Population: 1 enrolled subject withdrew participation before delivery. A second subject withdrew consent after delivery. 1 subject's neonate died due to extreme prematurity, which was unrelated to receiving the study drug.~Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects. Historical controls were not identified for this terminated study, thus this Outcome Measure cannot be reported.
Secondary
Hemoglobin Concentration Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Lactate Dehydrogenase Concentration Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Platelet Count Before and After Each Treatment.
Differences in the platelet count will be compared before treatment (ex. visit day 1) and after treatment in each participant receiving eculizumab.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Ratio of Urine Protein to Urine Creatinine Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Serious Adverse Events
Assessment of serious adverse events in eculizumab treatment arm compared with historical controls. 1. Neisseria meningitidis infection or development of invasive meningococcal disease, Neisseria gonorrhoeae, Neisseria sicca/subflava, and Neisseria spp unspecified and Aspergillus infections. 2. Graded clinical and laboratory abnormalities, according to the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS; DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\].
Time frame: 24 months
Population: 1 enrolled subject withdrew participation before delivery. A second subject withdrew consent after delivery.~Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects. Historical controls were not identified for this terminated study, thus this Outcome Measure cannot be reported.
Secondary
Serum Concentration of Placental Growth Factor (PlGF) Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Serum Concentration of Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Before and After Each Treatment.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Serum Creatinine Before and After Each Treatment.
Differences in the concentration of serum creatinine will be compared before treatment (ex. visit day 1) and after treatment in each participant receiving eculizumab.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
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.
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.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.
Secondary
Urine Protein Concentration Before and After Each Treatment.
Differences in urine protein concentration will be compared before treatment (ex. visit day 1) and after treatment in each participant receiving eculizumab.
Time frame: 24 months
Population: Assays for research lab samples were not done as the study was prematurely halted. Data supporting the primary and secondary outcomes were not collected from the two enrolled subjects, thus the data could not be reported.