Prospective Research in Infants With Mild Encephalopathy (PRIME)

• ClinicalTrials.gov Identifier: NCT01747863
• Recruitment Status: Completed
• First Posted: December 12, 2012
• Last Update Posted: September 25, 2017
• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Brown University; University of Texas Southwestern Medical Center; Wayne State University; Mahidol University; Ohio State University; Imperial College London
• Information provided by (Responsible Party): Guilherme Sant'Anna, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Hypoxic-Ischemic Encephalopathy; Brain Injury; Neonatal Seizure	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 Preliminary and unpublished observations from our group indicated that some infants who were not classified as moderate or severe NE had neurological abnormalities at discharge or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 Design

• Study Type: Observational
• Actual Enrollment: 63 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Prospective Research in Infants With Mild Encephalopathy: the PRIME Study.
• Study Start Date: December 2012
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: June 2017

Groups and Cohorts

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 </= 6 hrs of age, 24 hrs and at discharge home, (2) aEEG at 6 ± 3 hrs of age, (3) Brain MRI before discharge home to 30 days of age.

Outcome Measures

Primary Outcome Measures :

1. Percentage of infants with evidence of neurological dysfunction, brain injury and/or abnormality. [ Time Frame: 1 month ]

   Evidence of neurological dysfunction/injury/abnormality will be defined by any of these 3 criteria, as follows:

   1. MRI = Brain MRI score of pattern of injury (NICHD-NRN) > 0,
   2. aEEG = abnormal background pattern on aEEG (voltage or background pattern) at 6 ± 3 hrs of age.
   3. Any abnormality on the neurological at discharge exam.

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Long-term neurodevelopment [ Time Frame: 18-22 months of age ]
   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.

Eligibility Criteria

• Ages Eligible for Study: up to 6 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Locations

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

United States, Ohio

The Ohio Stage University - Nationwide Children's Hospital

Columbus, Ohio, United States, 43205-2664

United States, Rhode Island

Brown University

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern

Dallas, Texas, United States, 75235

Canada, Quebec

Montreal Children's Hospital

Montreal, Quebec, Canada, H3H 1P3

Thailand

Mahidol University - Ramathibodi Hospital

Bangkok, Thailand, 10400

United Kingdom

Imperial College London

London, United Kingdom, W12 0HS

Sponsors and Collaborators

McGill University Health Centre/Research Institute of the McGill University Health Centre

Brown University

University of Texas Southwestern Medical Center

Wayne State University

Mahidol University

Ohio State University

Imperial College London

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: Seetha Shankaran, MD; Wayne State 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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Guilherme Sant'Anna, Associate Professor of Pediatrics, McGill University Health Centre/Research Institute of the McGill University Health Centre
• ClinicalTrials.gov Identifier: NCT01747863
• Other Study ID Numbers: PRIME01; 12-108-PED ( Other Identifier: MUHC )
• First Posted: December 12, 2012
• Last Update Posted: September 25, 2017
• Last Verified: September 2017

Keywords provided by Guilherme Sant'Anna, McGill University Health Centre/Research Institute of the McGill University Health Centre:

Hypoxic Ischemic encephalopathy

Additional relevant MeSH terms:

Brain Injuries; Seizures; Brain Diseases; Brain Ischemia; Hypoxia-Ischemia, Brain; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Neurologic Manifestations; Hypoxia; Signs and Symptoms, Respiratory; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Hypoxia, Brain