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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Prospective Randomized Double-Blind, Placebo Controlled Evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia (PRESERVE-1)

Conditions
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Preeclampsia

Intervention / Treatment
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* Biological: Recombinant human antithrombin (ATryn)
* Other: Normal Saline 0.9%


Participation Criteria
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Eligibility Criteria
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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 occasions Oligohydramnios (deepest vertical pocket less than 2 x 2cm on ultrasound) Other maternal or fetal conditions that would preclude expectant management Known lethal or major fetal anomaly Recent (within 12 months) history of maternal alcoholism or drug dependence Diagnosis of epilepsy 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) 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 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 Multi-fetal pregnancy History of Antiphospholipid antibody syndrome Known hypersensitivity to goat and goat milk proteins Participation in another interventional clinical trial of an investigational, unapproved therapy (drug, biologic, device) within 30 days of consent

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Recombinant Human Antithrombin (ATryn)<br>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 | Biological: Recombinant human antithrombin (ATryn)<br>* 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<br>* Other names: Recombinant human antithrombin (rhAT);|
| Placebo Comparator: Normal Saline 0.9%<br>Placebo (Normal Saline 0.9%, matched for volume of active treatment) consisting of a loading dose over 15 minutes followed by continuous infusion. | Other: Normal Saline 0.9%<br>* Placebo Comparator: Normal Saline 0.9%<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in Gestational Age in Days | Increase in gestational age is defined as the gestational age at delivery minus the gestational age at randomization. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Measure of Specific Fetal and Neonatal Outcomes Based on Protocol Defined 5-point Scale (Scores of 0 to 4) | Composite score was calculated based on the following fetal and neonatal events: bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), cystic periventricular leucomalacia (PVL), retinopathy of prematurity (ROP), late Sepsis, necrotizing enterocolitis (NEC) and mortality (fetal and neonatal). The endpoint is measured on a 5 point scale where 0 represents no outcomes experienced and no mortality, and 4 represents death, as shown below. Should the same outcome occur more than once, it will only be counted once. Score Outcome 0 No events, no mortality One event, no mortality Two events, no mortality Three or more events, no mortality Death | Neonatal outcomes were assessed from birth until the later of 36 weeks (wks) Post Menstrual Age (PMA) and the 36 wks PMA visit, or through the 4-6 weeks post-delivery visit (if both 36 wks PMA and the 36 wks PMA visit occurred < 28 days post delivery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preeclampsia, Preterm preeclampsia, Pregnancy