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

March 19, 2020 updated by: Centre Hospitalier Universitaire de Saint Etienne

Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction. Randomized Multicenter Trial

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

82

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Brest, France
        • CHRU Brest
      • Clermont Ferrand, France, 63003
        • CHU Clermont-Ferrand
      • Grenoble, France, 38000
        • CHU Grenoble
      • Lyon, France
        • Ch Lyon Sud Pierre Benite
      • Lyon, France
        • HFME - Lyon Est
      • Lyon, France
        • Hôpital Croix Rousse Lyon
      • Roanne, France
        • CH Roanne
      • St Etienne, France, 42100
        • CHU Saint Etienne

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • Treatment
Other: Usual care
Patients will all benefit from the usual care
Other Names:
  • 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 Names:
  • Classic support

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Week 36

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in doppler parameters of uterine arterie
Time Frame: baseline from delivery
Doppler parameters is a composite outcome : pulsatility index and presence of notch
baseline from delivery
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
baseline from delivery
Change in doppler fetal weight
Time Frame: baseline from delivery
doppler fetal weight (grams)
baseline from delivery
birth weight
Time Frame: delivery
birth weight (grams)
delivery
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.
delivery
Number of fetal extraction
Time Frame: before 36 weeks of gestation
fetal extraction
before 36 weeks of gestation
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
1 month after delivery
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
1 month after delivery
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.
from randomisation to 1 month postpartum
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
From randomisation to 36 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire de Saint Etienne

Investigators

  • Principal Investigator: Tiphaine Raia-Barjat, MD, CHU Saint Etienne

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 22, 2016

Primary Completion (Actual)

September 5, 2019

Study Completion (Actual)

January 22, 2020

Study Registration Dates

First Submitted

January 28, 2016

First Submitted That Met QC Criteria

February 1, 2016

First Posted (Estimate)

February 3, 2016

Study Record Updates

Last Update Posted (Actual)

March 20, 2020

Last Update Submitted That Met QC Criteria

March 19, 2020

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1508175
  • 2016-000424-25 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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