Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia
Condition: Preeclampsia
MeSH terms: Pre-Eclampsia
Intervention: Recombinant human antithrombin (ATryn); Normal Saline 0.9%
Intervention description: Atryn 250 mg loading dose over 15 minutes, immediately followed by continuous infusion of 2000 mg per 24 hours. Total daily dose is 2250 mg for the first day and 2000 mg on subsequent days; Placebo Comparator: Normal Saline 0.9%
Intervention MeSH terms: Antithrombins; Antithrombin III
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 120.0
Sex: Female
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Preeclampsia; Preterm preeclampsia; Pregnancy

Summary:

      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.
    

Eligibility criteria:

        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