Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia (HEPEPE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00986765
First received: September 29, 2009
Last updated: August 5, 2013
Last verified: July 2013
  Purpose

Preeclampsia (PE) complicates 2-8% of pregnancies. It is associated with an increased risk of adverse maternal (death, eclampsia, abruptio placenta, HELLP syndrome) and perinatal (perinatal death, growth restriction, prematurity) outcomes. The only definite treatment of PE remains pregnancy termination. Therefore, prevention of PE remains an important challenge. Low dose aspirin may be used in the prevention of PE, particularly in women who had a severe preeclampsia before 34 weeks. Its efficiency, however, is very weak. Recently, it has been suggested that low molecular weight heparin might be useful in the prevention of PE.

The aim of this study is to analyze the usefulness of the enoxaparin 4000 UI/day in the prevention of a composite maternal or perinatal morbidity (occurrence of one of the following events: maternal death, PE, fetal growth retardation, abruptio placenta, perinatal death) in women who previously had a severe preeclampsia at less than 34 weeks' gestation. To answer this question, the investigators propose to conduct a multicenter prospective randomized trial that will compare two groups in parallel: a group where women will have an association of enoxaparin 4000 U/day and aspirin 100 mg/day and another group where women would have only aspirin 100 mg/day. The number of patients needed in each arm is 220.


Condition Intervention Phase
Preeclampsia
Drug: Lovenox® (enoxaparin)
Drug: Aspegic ® (Aspirin)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Low Molecular Weight Heparin, Enoxaparin, to Prevent Adverse Maternal and Perinatal Outcomes in Women With Previous Severe Preeclampsia at Less Than 34 Weeks' Gestation. A Prospective Randomized Trial

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • The primary outcome is a composite morbidity that may occur : maternal death, or perinatal death, or preeclampsia, or abruptio placenta, or fetal growth restriction. [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Recurrence of preeclampsia alone [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Recurrence of severe preeclampsia [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Fetal growth restriction alone [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Severe fetal growth restriction (< 5th percentile) [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Perinatal death alone [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Neonatal death [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Abruption alone [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Maternal death [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Fetal loss (10-21 weeks) [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Fetal death [ Time Frame: from 15 weeks to delivery ] [ Designated as safety issue: No ]
  • Recurrence of preeclampsia controlled for thrombophilia analysis (polymorphism of factor V Leiden, prothrombin G20210A gene polymorphism) [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Recurrence of preeclampsia controlled for angiogenic factors (free VEGF and PlGF, sFlt1, sEng) [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Neonatal morbidity (NICU transfer, length of hospitalization, mechanical ventilation > 24 hours, respiratory distress syndrome, necrotizing enterocolitis, periventricular leucomalacia, bronchopulmonary dysplasia, intraventricular hemorrhage grade III-IV) [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]
  • Enoxaparin toxicity: hemorrhage, skin reaction, thrombocytopenia (<100000/µL) related to heparin [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: Yes ]
  • Bone fracture [ Time Frame: from randomization until one month after the delivery ] [ Designated as safety issue: No ]

Estimated Enrollment: 255
Study Start Date: June 2009
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lovenox® , 4000 UI/day (+ Aspegic®)
Lovenox® (enoxaparin), 4000 UI/day (+ Aspegic® (Aspirin), 100 mg)
Drug: Lovenox® (enoxaparin)
Injectable solution 4000 UI
Other Name: Lovenox® (enoxaparin)
Active Comparator: Aspegic ®, 100 mg/day
Aspegic® (Aspirin),100 mg/day
Drug: Aspegic ® (Aspirin)
100 mg/day
Other Name: Aspegic ® (Aspirin)

  Hide Detailed Description

Detailed Description:
  1. Purpose of the study: To determine whether low molecular weight heparin (LMWH) enoxaparin decreases the rate of maternal and perinatal composite morbidity in women who previously had a severe preeclampsia that occurred at less than 34 weeks' gestation.
  2. Patients and methods: Multicenter, prospective, randomized trial comparing 2 groups of patients:

    • First group treated with aspirin 100 mg/day until 35 weeks' gestation and enoxaparin subcutaneous 4000 UI/day until delivery.
    • Second group treated with aspirin 100 mg/day alone until 35 weeks' gestation.

    At first prenatal visit between 7-13 weeks, inclusion and exclusion criteria will be searched. Randomization will be performed by internet software. It will be performed by center.

    After randomization at first prenatal visit patients will be allocated to aspirin-enoxaparin or aspirin alone as mentioned above. Enoxaparin will be stopped the day of delivery or after the occurrence of a complication that necessitates delivery. Pregnancy management will be performed as recommended by standard care. Each month, blood samples will be drawn for platelets count and the analysis of angiogenic factors (sFlt1, sEng, free PlGF and VEGF). In addition, blood sample will be drawn at first prenatal visit for thrombophilia work-up (Prot C, Factor V Leiden, Prothrombin gene polymorphism). Only results of platelet count will be given to local investigators during the study. All other analysis will be performed at the end of the study by Pr Gris at NIMES, and will be blinded to clinical results.

  3. Statistical analysis: Women with previous severe preeclampsia at less than 34 weeks' gestation have a 40% risk of occurrence of a composite morbidity (primary outcome defined above) at the next pregnancy. A 33% decrease of the composite morbidity defined above in women treated with LMWH enoxaparin is considered to be efficient. With an alpha risk of .05 and a beta risk of .20, the number of patients needed in each arm is 220. This trial will be analyzed as an "Intention to treat study". No interim analysis for the primary outcome will be performed. Results will be stratified by center.

    Primary outcome (categorical variable) will be analyzed by chi-square test. Secondary outcomes will analyzed by chi-square test for categorical variables or ANOVA for continuous variables.

    Statistical significance will be considered with a p value <.05. Statistical analysis will be performed by STATA software (StataCorp, 2003, TX).

  4. Registry of non-included patients: Each patient that has been non-eligible for the trial will be noted in a registry as well as the reason of exclusion.
  5. Independent committee for analysis of adverse outcome: An independent committee will analyze adverse maternal and perinatal outcomes before statistical analysis at the end of the study. This analysis will be blinded for the treatment allocated for the patients.
  6. Definitions:

    • Preeclampsia: Preeclampsia is defined by the association of gestational hypertension (after 20 weeks' gestation, a systolic blood pressure > 140 mmHg and/or a diastolic blood pressure > 90 mmHg, persistent at least at 4 hours apart, or a persistent diastolic blood pressure > 110 mmHg) and proteinuria (24 hours proteinuria > 300 mg, or at least 1+ persistent at least at 4 hours apart).
    • Fetal growth restriction: Fetal growth restriction is defined by a birthweight < 10th percentile.
    • Abruptio placentae: Abruptio placenta is defined by the association of bleeding and one of the following criteria:

      • Abnormal fetal heart rate,
      • Abdominal pain,
    • Perinatal death: Perinatal death is a death that occurs during fetal or neonatal Period, from 22 weeks' gestation until the 28th day of life.
    • Severe preeclampsia is defined, in a woman with preeclampsia, by the presence of one of the following criteria:

Maternal:

  • Severe hypertension (systolic blood pressure >160 MmHg and/or diastolic blood pressure > 110 mm Hg),
  • Persistent headaches or visual disturbances,
  • Persistent epigastric or RUQ pain,
  • 24 hours proteinuria ≥ 5gr,
  • Oliguria < 500 ml/24h, or serum creatinine > 120 µmol/L,
  • Eclampsia,
  • Pulmonary edema,
  • Abruption,
  • Platelet count < 100,000/ µL,
  • lactate dehydrogenase (LDH) > 600U/L, aspartate transaminase (ASAT) > 2 normal.

Fetal:

  • Severe fetal growth restriction (< 5ème percentile)
  • Severe Oligohydramnios.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient ≥ 18 years
  • Patient with a previous severe preeclampsia that occurred at less than 34 weeks' gestation
  • Patient between 7 and 13 weeks +6 days at first prenatal visit
  • Singleton pregnancy
  • Affiliation to social security
  • Informed consent given after receiving information on the study.

Exclusion Criteria:

  • Patient under law protection
  • Inability to sign written consent
  • Inability to follow the protocol because of a psychiatric disease
  • History of deep venous thromboembolism during previous pregnancy
  • Need of low molecular weight heparin during pregnancy
  • Previous arterial thrombosis
  • Patient having a cardiac valvular prosthesis that necessitates anticoagulation during pregnancy
  • Renal failure (creatinine clearance < 30 ml/min, or serum creatinine > 180 µmol/L
  • Previous hemorrhagic disease
  • A disease that might bleed (gastric ulcer)
  • Antiphospholipid antibody syndrome
  • Allergy to Aspirin
  • Allergy to heparins
  • Thrombocytopenia related to heparin use
  • Thrombocytopenia <100,000 /µL at first prenatal visit
  • Antecedent of osteoporosis
  • Inability to do subcutaneous injection of heparin
  • Weight > 100 kg
  • Patient included in another interventional trial
  • Patient positive for anti-phospholipids antibodies
  • Patient positive for HIV or HCV or HBS
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00986765

Contacts
Contact: Bassam Haddad (0)1 45 17 55 82 ext +33 Bassam.Haddad@chicreteil.fr
Contact: Fatiha Djennaoui (0)1 49 81 33 84 ext +33 fatiha.djennaoui@hmn.aphp.fr

Locations
France
Centre Hospitalier Intercommunal de Créteil Recruiting
Creteil, France
Contact: Bassam Haddad    (0)1 45 17 55 82 ext +33    Bassam.Haddad@chicreteil.fr   
Contact: Fatiha Djennaoui    (0) 1 49 81 33 84 ext +33    fatiha.djennaoui@hmn.aphp.fr   
Principal Investigator: Bassam Haddad         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Bassam Haddad Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00986765     History of Changes
Other Study ID Numbers: P071211
Study First Received: September 29, 2009
Last Updated: August 5, 2013
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Fetal growth restriction
Abruptio placentae
Perinatal death

Additional relevant MeSH terms:
Pre-Eclampsia
Hypertension, Pregnancy-Induced
Pregnancy Complications
Aspirin
Acetylsalicylic acid lysinate
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hematologic Agents
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 29, 2014