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

Preeclampsia Clinical Trial

— PRESERVE-1  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02059135
• Other study ID #: RB AT PPE 01-13
• Status: Completed
• Phase: Phase 3
• First received: February 6, 2014
• Last updated: February 7, 2017
• Start date: July 11, 2014
• Est. completion date: November 2016

Study information

• Verified date: February 2017
• Source: rEVO Biologics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: November 2016
• Est. primary completion date: May 18, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 16 Years and older

Eligibility

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]/IEC)

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

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Intervention

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:
• Normal Saline 0.9%
Placebo Comparator: Normal Saline 0.9%

Locations

Country	Name	City	State
United States	University of Alabama	Birmingham	Alabama
United States	Erlanger Medical Center	Chattanooga	Tennessee
United States	Northwestern University	Chicago	Illinois
United States	Tri-State Maternal Fetal Health	Cincinnati	Ohio
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	University Texas Medical Branch	Galveston	Texas
United States	University of Texas Houston School of Medicine	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Arkansas	Little Rock	Arkansas
United States	Norton Healthcare	Louisville	Kentucky
United States	University of South Alabama	Mobile	Alabama
United States	Intermountain Health	Murray	Utah
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Oschner Baptist	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of California at Irvine	Orange	California
United States	Women & Infants Hospital	Providence	Rhode Island
United States	Saint Louis University School of Medicine	Saint Louis	Missouri
United States	University of Utah Hospitals & Clinics	Salt Lake City	Utah
United States	Barnes-Jewish Hospital	St. Louis	Missouri
United States	University of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
rEVO Biologics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	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.	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
Primary	The primary outcome measure is the increase in gestational age.	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	The secondary outcome measure is a composite measure of specific fetal and neonatal outcomes.	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.	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.