Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia
Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia
The purpose of the study is to assess the efficacy, safety and pharmacokinetics (PK) of
 recombinant human antithrombin (ATryn) in addition to expectant management for the treatment
 of preterm preeclampsia (PPE). Efficacy will be assessed by comparing the difference in
 extension of gestational age from the time of randomization into the study until delivery
 between ATryn and placebo treated subjects. In addition, the effect of ATryn on fetal and
 neonatal clinical outcomes will be assessed. The PK characteristics of ATryn in the subjects
 will be investigated by measuring AT activity levels in the mother during treatment and in
 cord blood.
Hospitalized PPE patients who are being expectantly managed, after initial assessment and
 stabilization period, will be considered for the study. After informed consent has been
 obtained subjects will be screened for eligibility. Screening includes obtaining the
 subject's medical/obstetric history and a physical examination which includes an assessment
 of maternal and fetal status. Blood samples for hematology, clinical chemistries, biomarkers,
 coagulation, immunogenicity and AT activity levels will be drawn. Urine will be collected for
 baseline urinalysis, protein/creatinine ratio and biomarkers. Eligible subjects who meet
 inclusion/exclusion criteria will be randomized in a 1:1 ratio to receive a continuous
 infusion of either ATryn or placebo.

 Sampling for AT activity will be performed immediately prior to the first dose of study drug
 and at specified times thereafter.

 Subjects will continue on study drug until maternal and/or fetal indications for delivery
 necessitate cessation of expectant management or until 34 0/7 weeks of gestation. The average
 extension of pregnancy with standard of care expectant management in this patient population
 is approximately 7 days. It is assumed that treatment with ATryn will provide an additional
 increase in gestational age of 5-7 days as compared to this standard of care. Total duration
 on study drug is therefore estimated to be approximately 7 to 14 days on average.

 Post treatment assessments of the mother will be performed at hospital discharge and
 approximately 4-6 weeks after delivery of the neonate. Information on the neonates will be
 collected until they reach a post-menstrual age (PMA) of 36 weeks. If the neonate reaches 36
 weeks PMA < 28 days following delivery, the final neonatal follow-up visit should be done at
 the 4-6 week post-delivery visit.

 After the primary study completion and follow-up period, the neonate total number of days in
 the Neonatal Intensive Care Unit (NICU), days on a ventilator, days requiring supplemental
 oxygen (FiO2 ≥21%),the neonate hospital discharge date and whether the neonate is discharged
 from the hospital with a requirement for supplemental home oxygen therapy will be collected
 to help assess health care utilization. In addition, the date of death will be collected if
 the neonate expires before hospital discharge. These data will be considered supplemental to
 the primary study data set.
Inclusion Criteria:

 1. 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

 2. 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)

 3. 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

 4. In the opinion of the investigator the patient has demonstrated sufficient clinical
 stability to be eligible for expectant management

 5. The patient is expected to be managed as an inpatient until delivery

 6. Signed informed consent for both subject and neonate

 Exclusion Criteria:

 1. 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 occasions

 -  Oligohydramnios (deepest vertical pocket less than 2 x 2cm on ultrasound)

 -  Other maternal or fetal conditions that would preclude expectant management

 2. Known lethal or major fetal anomaly

 3. Recent (within 12 months) history of maternal alcoholism or drug dependence

 4. Diagnosis of epilepsy

 5. Has need for chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs)
 including selective cyclooxygenase (Cox)-2 inhibitors, or unwilling to abstain from
 use of NSAIDs during the study treatment period (low dose aspirin of 81 mg/day or less
 allowable)

 6. Received within 72 hours or has requirement for heparin; low molecular weight heparins
 such as enoxaparin or dalteparin; fondaparinux; antiplatelet agents such as
 clopidogrel, prasugrel, or high dose aspirin (>81 mg/day); Direct Thrombin Inhibitors
 (DTI) such as dabigatran

 7. Pre-existing renal disease, documented pre-pregnancy or in pregnancy prior to 20 weeks
 gestation (prior to the diagnosis of preeclampsia) or 24 hr urine of ≥0.3 gm/24 hours,
 documented in pregnancy, prior to 20 weeks gestation or ≥2+ dipstick or ≥ 0.3 Protein
 Creatinine Ratio (PCR), documented in pregnancy at the last available test prior to 20
 weeks gestation. In the case of conflicting results between dipstick, PCR, and timed
 urine collection tests to work up an episode of proteinuria, the timed urine
 collection result would supersede other results

 8. Multi-fetal pregnancy

 9. History of Antiphospholipid antibody syndrome

 10. Known hypersensitivity to goat and goat milk proteins

 11. Participation in another interventional clinical trial of an investigational,
 unapproved therapy (drug, biologic, device) within 30 days of consent