Clinical trial NCT02059135: Pharmacokinetics, Safety and Efficacy Study of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia
Official title: Prospective Randomized Double-Blind, Placebo Controlled Evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia (PRESERVE-1)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Preeclampsia
Keywords: Preeclampsia
Preterm preeclampsia
Pregnancy
Lead sponsor: rEVO Biologics
Sponsor class: INDUSTRY
First posted: 2014-02-11
Enrollment: 120
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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

Primary outcomes:
measure: Increase in Gestational Age in Days
timeFrame: 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 outcomes:
measure: Composite Measure of Specific Fetal and Neonatal Outcomes Based on Protocol Defined 5-point Scale (Scores of 0 to 4)
timeFrame: 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)
Other outcomes:
measure: Number of Participants Experiencing Individual Maternal, Perinatal and Neonatal Outcomes and Number of Participants Who Avoided All Neonatal Morbidity and Mortality
timeFrame: Maternal-till 4-6 weeks post delivery.Neonatal -birth until the later of 36 weeks PMA and the 36 weeks PMA visit, or through the 4-6 weeks post-delivery visit (if both 36 weeks PMA and the 36 weeks PMA visit occurred less than 28 days following delivery).
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Orange
country: United States
facility: University of California at Irvine
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: New Orleans
country: United States
facility: Oschner Baptist
state: Louisiana
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Tri-State Maternal Fetal Health
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Providence
country: United States
facility: Women & Infants Hospital
state: Rhode Island
city: Chattanooga
country: United States
facility: Erlanger Medical Center
state: Tennessee
city: Galveston
country: United States
facility: University Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: University of Texas Houston School of Medicine
state: Texas
city: Murray
country: United States
facility: Intermountain Health
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospitals & Clinics
state: Utah
Study officials:
affiliation: Yale New Haven Hospital
name: Michael Paidas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Paidas MJ, Tita ATN, Macones GA, Saade GA, Ehrenkranz RA, Triche EW, Streisand JB, Lam GK, Magann EF, Lewis DF, Dombrowski MP, Werner EF, Branch DW, Habli MA, Grotegut CA, Silver RM, Longo SA, Amon E, Cleary KL, How HY, Novotny SR, Grobman WA, Whiteman VE, Wing DA, Scifres CM, Sibai BM. Prospective, randomized, double-blind, placebo-controlled evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia. Am J Obstet Gynecol. 2020 Nov;223(5):739.e1-739.e13. doi: 10.1016/j.ajog.2020.08.004. Epub 2020 Aug 8.
citation: Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016 Apr;28(2):141-9. doi: 10.1097/MOP.0000000000000338.