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Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia (PRESERVE-1)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by rEVO Biologics
Sponsor:
Information provided by (Responsible Party):
rEVO Biologics
ClinicalTrials.gov Identifier:
NCT02059135
First received: February 6, 2014
Last updated: November 11, 2014
Last verified: October 2014

February 6, 2014
November 11, 2014
May 2014
August 2015   (final data collection date for primary outcome measure)
The primary outcome measure is the increase in gestational age. [ Time Frame: 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. ] [ Designated as safety issue: No ]
Increase in gestational age is defined as the gestational age at delivery minus the gestational age at randomization.
Same as current
Complete list of historical versions of study NCT02059135 on ClinicalTrials.gov Archive Site
The secondary outcome measure is a composite measure of specific fetal and neonatal outcomes. [ Time Frame: 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 and for the neonate until 36 weeks post menstrual age. ] [ Designated as safety issue: Yes ]
The specific fetal and neonatal outcomes include bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leucomalacia, retinopathy of prematurity, late Sepsis, necrotizing enterocolitis and mortality (fetal and neonatal). The outcome is measured on a 5 point scale.
Same as current
Other outcomes include individual maternal, perinatal and neonatal outcomes.In addition, a second neonatal composite outcome score, the avoidance of all morbidity and mortality will be examined [ Time Frame: 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 and for the neonate until 36 post menstrual age. ] [ Designated as safety issue: Yes ]
These outcomes will be summarized using counts and percentages, and exact (Clopper-Pearson) 95% confidence intervals for the true proportions will be calculated for each treatment.
Same as current
 
Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia
Prospective Randomized Double-Blind, Placebo Controlled Evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia (PRESERVE-1)

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 of 36 weeks.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Preeclampsia
Biological: Recombinant human antithrombin (ATryn)
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
Other Name: Recombinant human antithrombin (rhAT)
  • Active Comparator: Recombinant Human Antithrombin (ATryn)
    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
    Intervention: Biological: Recombinant human antithrombin (ATryn)
  • Placebo Comparator: Normal Saline 0.9%
    Placebo (Normal Saline 0.9%, matched for volume of active treatment) consisting of a loading dose over 15 minutes followed by continuous infusion.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
120
November 2015
August 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Hospitalized female pregnant patients of gestational age of ≥24 0/7 weeks to <28 0/7 weeks (based on an ultrasound performed prior to study enrollment)
  2. At least 16 years of age
  3. Recent diagnosis of Preeclampsia or Superimposed Preeclampsia in current hospitalization 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 (PCR) 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 or a doubling of the serum creatinine concentration 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 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 (PCR) 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 or a doubling of the serum creatinine concentration 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 (assessed just prior to decision to screen patient) that would likely require immediate delivery of the fetus:

    • 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 or a doubling of the serum creatinine concentration in the absence of other renal disease
    • 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
    • History of biophysical score ≤ 4/10 on 2 occasions
    • Oligohydramnios (deepest vertical pocket less than 2 x 2cm on ultrasound)
    • Intra uterine growth restriction (IUGR) < 5th percentile
    • 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. Received within last 7 days or has need for therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase (Cox)-2 inhibitors, or unwilling to abstain from use of NSAID's 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 PCR, documented in pregnancy at the last available test prior to 20 weeks gestation
  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 within 30 days of consent
Female
18 Years and older
No
Contact: Laura Massey, BS 508-370-5157 laura.massey@revobiologics.com
Contact: Denise Tilton, RN, MHA 508-370-5257 denise.tilton@revobiologics.com
United States
 
NCT02059135
RB AT PPE 01-13
Yes
rEVO Biologics
rEVO Biologics
Not Provided
Principal Investigator: Michael Paidas, MD Yale New Haven Health System Center for Healthcare Solutions
rEVO Biologics
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP