Prospective Research in Infants With Mild Encephalopathy (PRIME)

Prospective Research in Infants With Mild Encephalopathy: the PRIME Study.

A multicenter observational pilot study will be conducted to determine the natural history of infants with early diagnosis (≤ 6 hrs of age) of mild neonatal encephalopathy (NE) who are not qualified for therapeutic hypothermia. The intervention includes: neurologic examination by using modified Sarnat score at ≤ 6 hrs of age, 24 hrs and before discharge home, amplitude-integrated electroencephalography (aEEG) at 6 ± 3 hrs of age, brain MRI at before discharge home to 30 days of age and follow-up at 18-22 months of age. Primary outcome is the percentage of mild NE infants with evidence of brain injury defined by the presence of at least 1 abnormality of brain MRI, aEEG or neurologic examination in the neonatal period. Secondary outcome is the percentage of brain MRI, aEEG and neurological exam abnormalities, seizure, length of hospital stay, need of gavage feeds or gastrostomy at discharge home, death and long-term outcome.

Study Overview

• Status: Completed
• Conditions: Brain Injury; Hypoxic-Ischemic Encephalopathy; Neonatal Seizure
• Intervention / Treatment: Other: Neurologic examination

Detailed Description

Globally, an estimated 1.8 to 7.7 infants per 1000 live term births suffer from perinatal asphyxia, which remains an important cause of neonatal encephalopathy (NE) and neurodevelopmental impairment. Over the last six years, several randomized control trials have demonstrated that prolonged and moderate therapeutic hypothermia (TH) reduces the rate of death or disability at 18 months of age among infants who survived. In these trials, infants were eligible if there was evidence of perinatal hypoxia-ischemia and a moderate or severe degree of encephalopathy on neurological evaluation performed at ≤ 6 hrs of age. However, it has been recognized that the level of NE may change over time. Preliminary and unpublished observations from our group indicated that some infants who were not classified as moderate or severe NE had neurological abnormalities at discharge or evidence of brain injury on MRI performed during the neonatal period. Unfortunately, precise data on the outcomes of this specific population is not clear. Since TH is not offered to this population, the outcomes of infants that do not qualify for TH based on neurological evaluation performed ≤ 6 hrs of life requires a more precise investigation.

• Study Type: Observational
• Enrollment (Actual): 63

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital
• Thailand
  • Bangkok, Thailand, 10400
    • Mahidol University - Ramathibodi Hospital
• United Kingdom
  • London, United Kingdom, W12 0HS
    • Imperial College London
• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Ohio
    • Columbus, Ohio, United States, 43205-2664
      • The Ohio Stage University - Nationwide Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 hours (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infants with evidence of a perinatal event and NE who do not qualify for therapeutic hypothermia. NE will be defined as the presence of abnormal neurological findings on the modified Sarnat Score performed at ≤ 6 hrs of life. Evidence of a perinatal event will include criteria described in details in the whole body hypothermia trial (NEJM, 2005). The level of NE will be defined by the neurological exam performed by certified neonatologists working at the 6 centers.

Description

Inclusion Criteria:

• Infants with birth weight > or = 1800g and gestational age > or = 36 weeks AND
• Admission to neonatal intensive care unit (NICU) for possible hypothermia at < or = 6hr of life

Exclusion Criteria:

• Infants with normal neurological evaluation
• Major congenital abnormalities
• Refusal of informed consent
• Infants who receive passive or active cooling prior to the NICU admission
• Infants that develop seizures or moderate/severe NE within the first 24 hr of life and are initiated on therapeutic hypothermia after 6 hr of life.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Mild NE; Infants with evidence of a perinatal event and NE who do not qualify for therapeutic hypothermia.	Other: Neurologic examination; Neurologic examination includes: (1) neurologic examination using modify Sarnat score at

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of infants with evidence of neurological dysfunction, brain injury and/or abnormality.	Evidence of neurological dysfunction/injury/abnormality will be defined by any of these 3 criteria, as follows: MRI = Brain MRI score of pattern of injury (NICHD-NRN) > 0,; aEEG = abnormal background pattern on aEEG (voltage or background pattern) at 6 ± 3 hrs of age.; Any abnormality on the neurological at discharge exam.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of infants with seizures	Development of clinical or electrographic seizures	Participants will be followed for the duration of hospital stay, an expected average of 3 days
Length of hospital stay		Participants will be followed for the duration of hospital stay, an expected average of 3 days
Percentage of infants who need gavage feeds or gastrostomy at discharge home		Participants will be followed for the duration of hospital stay, an expected average of 3 days
Mortality rate	Death during the hospitalization	Participants will be followed for the duration of hospital stay, an expected average of 3 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term neurodevelopment	Long-term outcomes (18-22 months of age): Severe disability if there is a Bayley III Cognitive score < 70, severe cerebral palsy (CP), defined by the Gross Motor Function Classification System (GMFCS) grade level 3 to 5, blindness or profound hearing loss. Moderate disability will be defined as the Bayley Cognitive score is 70-84 and either seizures, moderate CP (defined by GMFCS grade level 2) or a hearing deficit requiring amplification to understand commands. Mild disability will be defined by a cognitive score 70-84, or a cognitive score ≥ 85 and either presence of mild or moderate CP (GMFCS grade levels 1 or 2), a seizure disorder or hearing loss with or without amplification. Normal will be defined as Bayley III Cognitive score ≥ 85 without any visual or hearing impairment, or CP.	18-22 months of age

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Wayne State University; Brown University; Imperial College London; Ohio State University; University of Texas Southwestern Medical Center; Mahidol University
• Investigators: Principal Investigator: Guilherme Sant'Anna, MD, McGill University; Principal Investigator: Lina Chalak, MD, University of Texas; Principal Investigator: Abbot Laptook, MD, Brown University; Principal Investigator: Chatchay Prempunpong, MD, Mahidol University; Principal Investigator: Sudhin Thayyil, MD, Imperial College London; Principal Investigator: Pablo Sanchez, MD, Ohio State University; Study Director: Pablo Sanchez, MD, The Ohio Stage University; Study Chair: Guilherme Sant'Anna, MD, McGill University

Publications and helpful links

General Publications

• Chalak LF, Adams-Huet B, Sant'Anna G. A Total Sarnat Score in Mild Hypoxic-ischemic Encephalopathy Can Detect Infants at Higher Risk of Disability. J Pediatr. 2019 Nov;214:217-221.e1. doi: 10.1016/j.jpeds.2019.06.026. Epub 2019 Jul 10. Erratum In: J Pediatr. 2020 Mar;218:e2.
• Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen KA, Mir I, Pappas A, Montaldo P, Thayyil S, Sanchez PJ, Shankaran S, Laptook AR, Sant'Anna G. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2018 Jan;38(1):80-85. doi: 10.1038/jp.2017.164. Epub 2017 Nov 2.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: December 7, 2012
• First Submitted That Met QC Criteria: December 10, 2012
• First Posted (Estimate): December 12, 2012

Study Record Updates

• Last Update Posted (Actual): September 25, 2017
• Last Update Submitted That Met QC Criteria: September 21, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Hypoxic Ischemic encephalopathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Signs and Symptoms, Respiratory; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Injuries; Seizures; Brain Diseases; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: PRIME01; 12-108-PED (Other Identifier: MUHC)