Long Term Prognostic of Neonatal Hypoxic Ischemic Encephalopathy With Hypothermia Treatment

Ischemic-Hypoxic Encephalopathy Clinical Trial

— LyTONEPAL  

Official title:

Long Term Prognostic of Neonatal Hypoxic Ischemic Encephalopathy in the Era of Neuroprotective Treatment With Hypothermia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02676063
• Other study ID #: DCIC1416
• Status: Active, not recruiting
• Start date: September 2015
• Est. completion date: March 2021

Study information

• Verified date: June 2018
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The primary objective is to evaluate neonatal characteristics, and biological and clinical investigations as predictive factors of death, or of severe and moderate neurodevelopmental disability at 3 years, in a large population-based cohort of full-term and late preterm neonates with moderate or severe HIE.

Contrary to most previous studies which have often analyzed the accuracy of one factor among all other clinical investigations, the investigators objective's is to seek a relevant combination of several factors among the following list:

• Neonatal characteristics: gestational age and birthweight, maternal disease, acute intrapartum event, delivery mode, acidosis, neurological examination, place of birth and neonatal transfer

• Laboratory investigations: pH, lactates and new biological markers as detailed below

• Clinical investigations: aEEG, EEG, MRI, diffusion-weighted MRI

Description:

Hypoxic-ischemic encephalopathy (HIE) is a rare neonatal condition affecting about 1‰ births and with a high rate of death and severe neurological disability despite significant improvement of the management of this illness in the last ten years. During the first hours and days of life, different examinations are made by neonatologists to guide decisions about the management of HIE and to provide information to families. Nevertheless, better knowledge about the early and late predictive factors of long-term severe and moderate neurodevelopmental outcomes is badly needed.

This study is a prospective national observational population-based study involving all level III intensive care units in France.

This population-based cohort study will be performed including all moderate or severe cases of HIE, occurring between 34 and 42 completed weeks gestation in newborns admitted to a neonatal intensive care unit of the participating French regions. Children will be followed-up until the age of 3 years.

Participating centers will be invited to adhere to current HIE management guidelines and/or clinical investigations considered optimal to date, to ensure standardize clinical practice. The study will ensure high quality data collection.

About indications, timing and characteristics of treatments and investigations will be elaborated by the scientific committee during the preparation stage of the cohort study. This professional advice will have the double advantage of enabling us to record more homogeneous and high-quality data, and to standardize and improve clinical management and investigations among newborns with HIE.

Within this main study, an ancillary study will be performed by 21 centers to address the first secondary objective (predictive value of very early - first 6 hours of life - neurological examination and biological investigations, including specific new biomarkers such as Interleukin-6, Metalloproteinase-9, TIMP-1, Albumin modified by hypoxia, troponin I, acylcarnitins and amino acids).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 800
• Est. completion date: March 2021
• Est. primary completion date: March 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Infants born at a gestational age of 34 weeks or more;

• Presenting early neurological distress with clinical signs of moderate to severe HIE at a standardized neurologic examination performed by a senior examiner:

• Moderate HIE: lethargy, hyper-reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro reflex

• Severe HIE: stupor, flaccidity, small to mid-position pupils that react poorly to light, reduced stretch reflexes, hypothermia or no Moro reflex

• With criteria for asphyxia:

• pH of 7.0 or less or a base deficit of 16 mmol per liter or more in a sample of umbilical-cord blood or any blood sampled in the first hour after birth.

• If, during this interval, the pH is between 7.01 and 7.15, base deficit is between 10 and 15.9 mmol per liter, or blood gas is not available, additional criteria will be required. These include:

• an acute perinatal event (e.g., late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage, or cardiorespiratory arrest)

• or an abrupt change in fetal heart rate (FHR), defined as a persistent abnormal FHE after a period of normal tracing: bradycardia or prolonged deceleration, persistent variable decelerations, persistent late decelerations, and reduced heart variability

• or either a 10-minute Apgar score of 5 or less or assisted ventilation initiated at birth and continued for at least 10 minutes.

• Written parental informed consent

• Covered by the French social security

Exclusion Criteria:

• Congenital malformations

• Chromosomal disorders

• Congenital neuromuscular disorders

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypothermia
• Hypoxia
• Hypoxia, Brain
• Hypoxia-Ischemia, Brain
• Ischemia
• Ischemic-Hypoxic Encephalopathy

Locations

Country	Name	City	State
France	Chu Amiens	Amiens
France	Chu Besancon	Besançon
France	Chu Bordeaux	Bordeaux
France	Chu Brest	Brest
France	CHU CAEN	Caen
France	CHU Clermond-Ferrand	Clermont-Ferrand
France	Chi Creteil	Creteil
France	Chu Dijon	Dijon
France	CHU FORT de France	Fort De France
France	Chu Grenoble	Grenoble
France	Chru Lille	Lille
France	Chu Limoges	Limoges
France	Chu Marseille	Marseille
France	CHU Montpellier	Montpellier
France	Chu La Miletrie	Poitiers
France	Chu Reims	Reims
France	Chu Rouen	Rouen
France	CHU St Denis	Saint-Denis De La Réunion
France	CHU St Pierre	Saint-Pierre
France	Chu Strasbourg	Strasbourg
France	Chu Toulouse	Toulouse
France	Chu Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (4)

Fenichel GM. Hypoxic-ischemic encephalopathy in the newborn. Arch Neurol. 1983 May;40(5):261-6. Review. — View Citation

Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Hum Dev. 1985 May;11(1):21-6. — View Citation

Use and abuse of the Apgar score. Committee on Fetus and Newborn, American Academy of Pediatrics, and Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Pediatrics. 1996 Jul;98(1):141-2. — View Citation

Volpe JJ. Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol. 2012 Aug;72(2):156-66. doi: 10.1002/ana.23647. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome measure is a combined criterion : death, neurodevelopmental disabilities in survivors	A combined criterion which includes: Death between birth and 3 years of age; Neurodevelopmental disabilities in survivors, defined as : o Severe disabilities; Intellectual impairment with a mental score >2SD below the mean or <70 (ASQ); Or Cerebral palsy with a Gross Motor Function level of 3-5 according to the GMFCS; Or bilateral blindness (vision <20/200 acuity); Or deafness requiring amplification (>60dB)and/; Or a persistent disorder defined as recurrent seizures after discharge from neonatal intensive care requiring anti-convulsion therapy at the examination time point; o Moderate disabilities; Intellectual impairment with a mental score >1SD below the mean or 70 to 84 (ASQ); Cerebral palsy with a Gross Motor Function level of 1 or 2 according to the GMFCS; Or hearing impairment requiring no amplification	between birth and 3 years of age
Secondary	First secondary objective : The relevance of specific new biomarkers : Protein levels (IL-6, MMP-9, TIMP-1, Albumine modified by hypoxia, troponine I), acylcarnitins and amino acids.	The biologist will evaluate the relevance of specific new biomarkers : Protein levels (IL-6, MMP-9, TIMP-1, Albumine modified by hypoxia, troponine I) unites will be determined using an ELISA; the measurement of acylcarnitins and amino acids by tandem liquid phase chromatography coupled with mass spectroscopy.; The analyses will be blinded and centralized to Reims University laboratory	before H6 and at 3 days
Secondary	Second secondary objective: the predictive value of clinical investigations during the first weeks of life and treatments.	To analyze the predictive value of clinical investigations during the first weeks of life and treatments, including cooling: for normal outcomes (absence of death, any disability, any epilepsy or any need for physiotherapy, orthophonist or psychologist or other measures of reeducation), moderate or severe neurodevelopmental disabilities, and death; At 18 months and 3 years of age; In this part, we will assess the ability of a normal developmental assessment at 18 months to predict survival free of disability or retardation at 3 years. This information will be useful in the future to define different strategies of follow up according to the assessment at 18 months of age.	first week, At 18 months and 3 years of age
Secondary	Third secondary objective : Number and percentage of participants with cooling.	The third secondary objective is analyzed thanks to : number of patients with method of cooling : Criticool, tecotherm, craft, other; duration of cooling in hours; number of severe or modere HIE according to the Sarnat classification; time to initiate cooling in minutes	birth
Secondary	Fourth secondary objective : Number and percentage of various obstetrical conditions leading to the worse outcomes	Number and percentage of : Maternal pyrexia,; a persistent occipito-posterior position,; an acute intrapartum event (hemorrhage, maternal convulsions, rupture of uterus, snapped cord, and birth of baby before arrival at obstetric facility),; an instrumental vaginal delivery; an emergency caesarean section	birth