Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia

Inclusion Criteria

• Hospitalized female pregnant patients of gestational age of ≥23 0/7 weeks to ≤30 0/7 weeks (for subjects at gestational age 23 0/7 to 23 6/7 all standard interventions including antenatal steroids and cesarean for fetal indications must be offered).

Gestational age determination by local practice using one of the following three approaches:

• Last menstrual period (LMP) dating and confirmatory ultrasound
• Ultrasound alone when LMP is not reliable
• Known date of conception in the setting of assisted reproductive technology
• At least 16 years of age (NOTE: different age restrictions may apply per local regulation and/or ethical considerations; subjects under the local age of consent may be excluded at the discretion of the reviewing Institutional Review Board (IRB)
• Recent diagnosis of Preeclampsia or Superimposed Preeclampsia as defined by:
• For Preeclampsia
• Gestational hypertension defined as a recorded systolic blood pressure (BP) of

≥140 mm Hg or diastolic BP of ≥90 mm Hg on 2 occasions at least 4 hours apart (since the commencement of medical intervention in any facility) OR

• Severe gestational hypertension defined as systolic blood pressure of ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg, confirmed with second assessment within a short interval (minutes) AND
• New onset of any of the following:
• Proteinuria defined as ≥0.3 g protein per 24 hours in a 12-24 hour urine collection or protein/creatinine ratio of ≥0.3 mg/mg* (on a random sample or any collection period.)
• Platelet count less than 100,000/μL
• Serum creatinine concentrations greater than 1.1 mg/dL in the absence of other renal disease
• Elevated liver transaminases to ≥ twice upper limit of normal
• Cerebral or visual symptoms

For Superimposed preeclampsia:

• The start of antihypertensive medication, increasing the dose of a currently administered antihypertensive medication or adding a second antihypertensive medication after 20 weeks of pregnancy for systolic BP ≥ 160 or diastolic BP ≥ 105 in a patient that had a previous history of controlled hypertension before 20 weeks of pregnancy. AND
• New onset of any of the following:
• proteinuria defined as ≥0.3 g protein per 24 hours in a 12-24 hour urine collection or protein/creatinine ratio of ≥0.3 mg/mg (on a random sample or any collection period)
• Platelet count less than 100,000/μL
• Serum creatinine concentrations greater than 1.1 mg/dL in the absence of other renal disease
• Elevated liver transaminases to ≥ twice upper limit of normal
• Cerebral or visual symptoms
• In the opinion of the investigator the patient has demonstrated sufficient clinical stability to be eligible for expectant management
• The patient is expected to be managed as an inpatient until delivery
• Signed informed consent for both subject and neonate

Exclusion Criteria

• Criteria that would likely require immediate delivery of the fetus are exclusionary if present just prior to randomization:
• Refractory hypertension despite maximal medical intervention of systolic BP ≥160 mm Hg or diastolic BP of ≥110 mm Hg
• Thrombocytopenia (platelets ˂ 100/mm3) with or without Hemolysis elevated liver enzymes low platelets (HELLP) syndrome defined as defined as Aspartate amino transferase (AST) ≥70 units/L, and platelets ˂100/mm3, and evidence of hemolysis on blood film plus either Lactic dehydrogenase (LDH) ≥600 IU/mL or total bilirubin ≥1.2 mg/dL)
• Oliguria (≤500 mL/24 hours) or evidence of progressive renal insufficiency
• Serum creatinine concentration greater than 1.1 mg/dL
• Persistent visual disturbances
• Placental abruption
• Pulmonary edema
• Nonreassuring fetal heart rate tracing
• Intractable headache unrelieved with analgesia
• Intractable right upper quadrant abdominal pain or vomiting
• If umbilical Doppler ultrasound has been performed, the presence of an abnormal umbilical artery Doppler as defined by absent or reverse end diastolic flow
• Biophysical score ≤ 4/10 on 2 occ