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

NCT02059135 | Completed Phase 3 Results DMC

• 1 other identifier: RB AT PPE 01-13
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 23

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.

Conditions

Preeclampsia

Keywords

Preeclampsia; Preterm preeclampsia; Pregnancy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Composite Measure of Specific Fetal and Neonatal Outcomes Based on Protocol Defined 5-point Scale (Scores of 0 to 4)

  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 (1)

• Number of Participants Experiencing Individual Maternal, Perinatal and Neonatal Outcomes and Number of Participants Who Avoided All Neonatal Morbidity and Mortality

  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).

Study Arms (2)

Recombinant Human Antithrombin (ATryn)

ACTIVE COMPARATOR

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)

Normal Saline 0.9%

PLACEBO COMPARATOR

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%

Interventions

Recombinant human antithrombin (ATryn) BIOLOGICAL

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

Also known as: Recombinant human antithrombin (rhAT)

Recombinant Human Antithrombin (ATryn)

Normal Saline 0.9% OTHER

Placebo Comparator: Normal Saline 0.9%

Also known as: Normal Saline

Normal Saline 0.9%

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• rEVO Biologics: lead

Study Sites (23)

University of Alabama

Birmingham, Alabama, 35210, United States

Location

University of South Alabama

Mobile, Alabama, 36604, United States

Location

University of Arkansas

Little Rock, Arkansas, 72204, United States

Location

University of California at Irvine

Orange, California, 92868, United States

Location

Yale New Haven Hospital

New Haven, Connecticut, 06519, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Norton Healthcare

Louisville, Kentucky, 40202, United States

Location

Oschner Baptist

New Orleans, Louisiana, 70112, United States

Location

Saint John Hospital and Medical Center

Detroit, Michigan, 48236, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 32916, United States

Location

Barnes-Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Saint Louis University School of Medicine

St Louis, Missouri, 63117, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

Tri-State Maternal Fetal Health

Cincinnati, Ohio, 45211, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Women & Infants Hospital

Providence, Rhode Island, 02905, United States

Location

Erlanger Medical Center

Chattanooga, Tennessee, 347403, United States

Location

University Texas Medical Branch

Galveston, Texas, 77555, United States

Location

University of Texas Houston School of Medicine

Houston, Texas, 77030, United States

Location

Intermountain Health

Murray, Utah, 84107, United States

Location

University of Utah Hospitals & Clinics

Salt Lake City, Utah, 84132, United States

Location

Related Publications (2)

• 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.

  PMID: 32780999 DERIVED

• Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016 Apr;28(2):141-9. doi: 10.1097/MOP.0000000000000338.

  PMID: 26886785 DERIVED

MeSH Terms

Conditions

Pre-Eclampsia

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Limitations and Caveats

Note: 6 subjects (2 in the Recombinant Human Antithrombin (ATryn) group and 4 in the placebo group) were randomized but received no treatment. These subjects are included in the ITT population but not the maternal safety population.

Results Point of Contact

• Title: Laura Massey, Sr. Clinical Project Manager
• Organization: LFB USA

laura.massey@lfb-usa.com

508-370-5157

Study Officials

• Michael Paidas, MD

  Yale New Haven Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2014
• First Posted: February 11, 2014
• Study Start: July 11, 2014
• Primary Completion: May 18, 2016
• Study Completion: November 1, 2016
• Last Updated: August 9, 2017
• Results First Posted: August 9, 2017

Record last verified: 2017-07

Locations

US (23)