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Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction (GROWTH)

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ClinicalTrials.gov Identifier: NCT02672566
Recruitment Status : Recruiting
First Posted : February 3, 2016
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Saint Etienne

Brief Summary:

Intrauterine growth restriction (IUGR) is correlated to an abnormal placenta development, with an alteration of the maternal-fetal circulation, coagulation troubles, and apparition of placental infarcts. IUGR represents the third cause of perinatal mortality in France, and is associated to an important morbidity. For birth-weights < 10th percentile of the gestational age, the neonatal death risk is doubled, compared to abnormal weights. In 35% of cases, IUGR is of vascular origin and is included in the broader framework of placental vascular pathology (PVP).

Up to now, studies have focused on the primary or secondary prevention of PVP. Few studies have evaluated the treatment of constituted vascular IUGR. Currently, the management of vascular IUGR is mainly based on active surveillance, or termination of pregnancy. Pathological findings suggest that placental pro-thrombotic phenomena play a role in the constitution of vascular IUGR. Since aspirin is not effective in reducing this type of event, a randomized, open-label study conducted in China compared 14-day treatment with low-molecular-weight heparin (LMWH) versus Dan-Shen (a product not used in France) after diagnosis of IUGR. This trial, including 73 patients, showed a significant improvement in average growth kinetics in the LMWH group. The mean birth weight was 2877 g in the heparin group and 2492 g in the Dan-Shen group (p <0.0001). However, no data were provided concerning the number of newborns with a birth weight <10th percentile, i.e. the risk of morbidity and mortality, or complications occurring. Due to the lack of reliable data, LMWH are not included in the currently recommended therapeutic strategy for vascular IUGR.

The studies in IUGR reported to date mainly focused on primary or secondary prevention in women at risk of PVP, assessing the value of aspirin, which showed only a modest effect. No effective therapeutic strategy is available to treat patients with constituted vascular IUGR, a situation where LMWH should be more effective than antiplatelets given the vascular context.


Condition or disease Intervention/treatment Phase
Fetal Growth Retardation Drug: Enoxaparin Other: Usual care Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction. Randomized Multicenter Trial
Actual Study Start Date : July 22, 2016
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Heparin

Arm Intervention/treatment
Experimental: Experimental group : enoxaparin
Experimental group will take enoxaparin (4000 Ui / Day) and will benefit from the usual care.
Drug: Enoxaparin
Enoxaparin will be delivered to the patients every day at the dose of 4 000 Ui.
Other Name: Treatment

Other: Usual care
Patients will all benefit from the usual care
Other Name: Classic support

Active Comparator: Control group
The control group will only benefit from the usual care.
Other: Usual care
Patients will all benefit from the usual care
Other Name: Classic support




Primary Outcome Measures :
  1. Number of new born with a weight inferior at the 10th percentile [ Time Frame: Week 36 ]
    With the AUDIPOG formula, the number of new born with a weight inferior at the 10th percentile will be calculated.


Secondary Outcome Measures :
  1. Change in doppler parameters of uterine arterie [ Time Frame: baseline from delivery ]
    Doppler parameters is a composite outcome : pulsatility index and presence of notch

  2. Change in doppler parameters of ombilical arterie [ Time Frame: baseline from delivery ]
    Doppler parameters is a composite outcome : resistance index, presence of a zero diastole or reverse flow

  3. Change in doppler fetal weight [ Time Frame: baseline from delivery ]
    doppler fetal weight (grams)

  4. birth weight [ Time Frame: delivery ]
    birth weight (grams)

  5. Number of new born with a weight inferior at the 3rd percentile [ Time Frame: delivery ]
    With the AUDIPOG formula, the number of new born with a weight inferior at the 3rd percentile will be calculated.

  6. Number of fetal extraction [ Time Frame: before 36 weeks of gestation ]
    fetal extraction

  7. number of major neonatal parameters [ Time Frame: 1 month after delivery ]
    Major neonatal parameters is at least one or more : Perinatal death, Ischemic encephalopathy Major intra- or periventricular bleeding (grade 3 or 4), Periventricular leukomalacia, Necrotizing enterocolitis, Bronchopulmonary dysplasia or Sepsis

  8. number of minor neonatal parameters [ Time Frame: 1 month after delivery ]
    Minor neonatal parameters is a composite outcome : Caesarean section for fetal distress, Cord arterial pH < 7.1, Apgar score <7 at 5 minutes

  9. Number of Major bleeding events (MB) and clinically relevant non-major bleeding events (CRNMB) [ Time Frame: from randomisation to 1 month postpartum ]
    The definitions of major bleeding events and clinically major bleeding events are adapted from the ISTH definition for which were added a specific Obstetrics and Gynaecology definition Bleeding events (MB) is a composite outcome.

  10. Number of thrombocytopenia [ Time Frame: From randomisation to 36 weeks ]
    thrombocytopenia is a composite outcome : Thrombopenia defined by platelet count < 100 G/L Significant thrombocytopenia with HIT suspicion defined as follows:≥ 40% decline of the platelet count (compared with baseline value) occurring during the first 8 weeks following the start of HBPM Or platelet count < 80 Giga/l to terme



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient over 18 years being at a gestational age ≥ 22 and <34 weeks of gestation with vascular fetal growth retardation defined according CNGOF
  • Ultrasound Estimated fetal weight below the 10th percentile
  • Clinical and ultrasound findings suggesting pathologically impaired growth or diminished foetal well-being
  • Clinical and ultrasound findings suggesting placental insufficiency
  • Precise dating of pregnancy with an ultrasound between 11 + 0 and 13 + 6 weeks of gestation
  • Written informed consent

Exclusion Criteria:

  • multiple pregnancy or identified cause of IUGR (intra-uterine growth retardation)
  • Patient with an immediate indication of fetal extraction
  • Women with a history of venous thromboembolism or already treated with anti-coagulant
  • Women with a contraindication to enoxaparin treatment at prophylactic doses
  • Patient refusing to participate or unable to consent
  • Patient with less than 80,000 platelets / mm 3 with the initial assessment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02672566


Contacts
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Contact: Tiphaine Raia-Barjat, MD tiphaine.barjat@gmail.com
Contact: Florence Rancon, CRA florence.rancon@chu-st-etienne.fr

Locations
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France
Chru Brest Recruiting
Brest, France
Contact: Philippe Merviel, MD         
Principal Investigator: Philippe Merviel, MD         
Sub-Investigator: Jacob Hannigsberg, MD         
Sub-Investigator: Christophe Trémouilhac, MD         
Sub-Investigator: Anne-Hélène Saliou, MD         
Chu Clermont-Ferrand Recruiting
Clermont Ferrand, France, 63003
Contact: Didier Lemery, MD         
Principal Investigator: Denis Gallot, MD         
Sub-Investigator: Helene Laurichesse, MD         
Sub-Investigator: Marie, Cécile Accoceberry, MD         
Sub-Investigator: Dominique Juillard, MD         
Sub-Investigator: Amélie Delabaere, MD         
Sub-Investigator: Emmanuelle Boulay, MD         
Sub-Investigator: Lucie Jaillet, MD         
Sub-Investigator: Clément Bruhat, MD         
Sub-Investigator: Marie Herault, MD         
Chu Grenoble Recruiting
Grenoble, France, 38000
Contact: Pascale Hoffmann, MD         
Principal Investigator: Pascale Hoffmann, MD         
Sub-Investigator: Véronique Equy, MD         
Sub-Investigator: Anne-Laure Coston, MD         
Sub-Investigator: Catherine Thong Vanh, MD         
Ch Lyon Sud Pierre Benite Recruiting
Lyon, France
Contact: Olivier Dupuis, MD         
Principal Investigator: Olivier Dupuis, MD         
Sub-Investigator: Simon Ducoulombier, MD         
Sub-Investigator: Lucie Bonin, MD         
HFME - Lyon Est Recruiting
Lyon, France
Contact: Muriel Doret, MD         
Principal Investigator: Muriel Doret, MD         
Sub-Investigator: Mona Massoud Nassour, MD         
Hopital Croix Rousse Lyon Recruiting
Lyon, France
Contact: Cyril Houissoud, MD         
Principal Investigator: Cyril Houissoud, MD         
Sub-Investigator: Jonathan Caloone, MD         
Ch Roanne Suspended
Roanne, France
Chu Saint Etienne Recruiting
St Etienne, France, 42100
Contact: Tiphaine Raia-Barjat, MD         
Principal Investigator: Tiphaine Raia-Barjat, MD         
Sub-Investigator: Céline Chauleur, MD         
Sub-Investigator: Céline Fanget, MD         
Sub-Investigator: Amandine Stadler, MD         
Sub-Investigator: Edouard Noblot, MD         
Sub-Investigator: Anne Genod, MD         
Sub-Investigator: Marianne Perrot, MD         
Sub-Investigator: Marie-Noëlle Varlet, MD         
Sub-Investigator: Charlotte Vermersch, MD         
Sub-Investigator: Suzanne Lima, MD         
Sub-Investigator: Laura Chauveau, MD         
Sponsors and Collaborators
Centre Hospitalier Universitaire de Saint Etienne
Investigators
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Principal Investigator: Tiphaine Raia-Barjat, MD CHU SAINT ETIENNE

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Responsible Party: Centre Hospitalier Universitaire de Saint Etienne
ClinicalTrials.gov Identifier: NCT02672566     History of Changes
Other Study ID Numbers: 1508175
2016‐000424‐25 ( EudraCT Number )
First Posted: February 3, 2016    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:
Fetal Growth Retardation
enoxaparin

Additional relevant MeSH terms:
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Fetal Growth Retardation
Fetal Diseases
Pregnancy Complications
Growth Disorders
Pathologic Processes
Heparin
Heparin, Low-Molecular-Weight
Dalteparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action