Ignite Creation Date:
2024-05-06 @ 8:28 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06394453
Status:
RECRUITING
Last Update Posted:
2024-05-01
First Post:
2024-04-20
Brief Title:
Is Feeding During Therapeutic Hypothermia Safe and Can Improve Outcomes in Infants With Hypoxic-ischaemic Encephalopathy
Sponsor:
Nutricia Foundation
Organization:
Nutricia Foundation
Study Overview
Official Title:
Is Feeding During Therapeutic Hypothermia Safe and Can Improve Outcomes in Infants With Hypoxic-ischaemic Encephalopathy a Randomized Controlled Study
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Therapeutic hypothermia TH is the standard of care for newborns with moderate to severe hypoxic-ischaemic encephalopathy HIE born at 35 weeks or more of gestation Many neonatal units do not use enteral feeding during TH in fear of increased risk of complications Withholding enteral feedings during TH lacks supporting evidence The aim of the study is to determine if enteral feeding during TH in patients with HIE is safe and assess its effects Investigators will perform multicenter randomized controlled study in level III neonatal intensive care units on infants qualified for TH Infants will be randomized into 2 groups 1 unfed during 72 hours of TH 2 fed group which will start receive enteral feeding with mother milk or human donor breast milk at 10 mlkgday during first day of TH 20 mlkgday during second day 30 mlkgday during third day The primary outcome will be 1 combined necrotizing enterocolitis or death 2 length of hospital stay The secondary outcomes will be 1 time to full enteral feeding 2 late-onset sepsis 3 Test of Infant Motor Performance scoring 4 MRI scoring 5 MR spectroscopy parameters
Detailed Description:
Investigators will perform a multi-centre randomized parallel-arm study in level III neonatal intensive care units in southern part of Poland Małopolska - 3 units and Podkarpacie - 2 units on infants qualified for TH A randomization of subjects will be done via computer software Redcap Randomization Module Participants will be allocated to an intervention THhuman milk HM or control TH group In both groups standard therapeutic hypothermia to rectal temperature of 335 C will be performed by 72 hours including during neonatal transport for outborn babies starting within 6 hours after birth Investigators will use mother milk or human donor breast milk if mother milk is not available
1 Inclusion criteria
1 35 weeks or more gestational age
2 6 hours post birth
3 Any of the following
Metabolic or mixed acidosis with a pH of 70 or a base deficit 16 mmolL in an umbilical cord blood sample or any blood obtained within first hour after birth
10-minute Apgar score of 5
Ongoing resuscitation initiated at birth and continued for 10 minutes
4 Moderate to severe encephalopathy on clinical examination using a Thompson HIE score 7
5 Signed informed consent by parent
2 Exclusion criteria
1 Critical general condition
2 Aneuploidies 13 th 18 th 21 st
3 Birth weight 1800 g
4 Severe congenital defects with poor prognosis
5 Severe mechanical head injuries
6 Congenital malformations of digestive system esophageal atresia duodenal atresia gastroschisis omphalocele anal atresia
All eligible newborns will be randomized to one of the two groups
1 unfed during 72 hours of TH control group
2 fed group which will start receiving enteral feeding with mother milk or human donor breast milk at 10 mlkgday during first day of TH 20 mlkgday during second day and 30 mlkgday during third day experimental group
Both groups will be receiving parenteral nutrition PN from day one onwards Parenteral nutrition will be defined as receiving any type of nutrient solution in any volume through any route of administration peripheral venous cannula central venous catheter or umbilical catheter As the volume of enteral feeding will be increased the volume of PN will be decreased gradually
During the feeding process participants will be routinely checked up for the signs of feeding intolerance or NEC Feeding intolerance FI will be defined with the presence of one or more of these criteria 1 gastric residuals 50 on a single occasion among participants who received nosogastric feeds 2 biliousbloody gastric residuals among participants who received nosogastric feeds 3 abdominal distension increase in abdominal girth by 2 cm from baseline 4 emesis 5 gross or occult blood in the stool
Necrotizing enterocolitis NEC Bell stage 2 or 3 will be diagnosed based on the presence of one or more of the clinical signs bilious gastric aspirate or emesis abdominal distension occult or gross blood in stool and the presence of at least one of the following sonographic findings 1 pneumatosis intestinalis 2 portal vein gas andor 3 pneumoperitoneum
The criteria for stopping the trial intervention 1 any serious adverse events for enteral feeds mainly including NEC 2 infant developed severeunstable condition eg severe pulmonary hypertension which lead to stop TH and fasting must last for more than 24 hours
Primary endpoints 1 Combined Necrotizing enterocolitis or death Necrotizing enterocolitis will be defined by the modified Bells staging criteria stage II or stage III
2 Length of hospital stay assessed as duration of time spent in hospital before discharge measured in days
Secondary endpoints 1 Time to full enteral feeding full enteral feeding defined as participants receive all of their prescribed nutrition as milk feeds and do not receive any supplemental parenteral fluids or nutrition 2 Late-onset sepsis defined as sepsis occurring at or after 72 hours of life 3 Test of Infant Motor Performance scoring 4 MRI scoring using MRI scoring system by Rutherford et al classifying the severity of injury in the basal ganglia and thalami BGT cortex CX white matter WM each on a scale of 0-3 and posterior limb of the internal capsule PLIC scale 0-2 the higher number indicating more severe abnormality Total injury score TIS will be the sum of these regional scores scale of 0-11
5 MR spectroscopy parameters such as LacNAA LacCr NAACr CHONAA Primary outcomes are reduction of mortality or NEC stage 2 or 3 and length of hospital stay Investigators assumed that 50 difference as being a clinically significant Estimated that 43 children in each group are needed to achieve a significant difference with a power of 90 along with a two-sided 5 significance level Given the anticipated dropout rate of 20 52 subjects are necessary in each group
Participants will be randomly assigned to either control or experimental group with a 11 allocation based on a computer-generated randomization Redcap Caregivers of the participants will remain unblinded The researchers and the statistician will be blinded until the end of the study
The analyses will be performed after last patient out after monitoring and cleaning of data gathered from all patients Analyses will be performed by the investigators and statistician using the latest version of Medcalc statistics software
The flow of participants will be illustrated in a flow diagram according the Consolidation Standard of Reporting Trials CONSORT
The main analysis will be performed according the intention-to-treat ITT principle
The baseline characteristics of the included patients will be reported per randomization group and shown in a baseline table Dichotomous variables will be summarised as proportion of patients with the count divided by the total number of evaluated patients Continuous variables will be summarised as mean with standard deviation in case of normal distribution and as median with interquartile range in case of non-normal distribution Testing for normality of data distributions will be based on the Shapiro-Wilks test For continuous variables a footnote will state the number of evaluated patients Differences in baseline characteristics between study arms will be reported as preferred by the intended journal Differences between the study arms will be analysed using Fisher test independent t test or Mann-Whitney test if required by the journal
The assessment and analysis of the primary and secondary outcomes will be discussed separately All continuous data will be checked for normality For continuous outcomes the mean difference MD and for dichotomous outcomes the relative risk RR will be calculated The difference between study groups will be considered statistical significant when the p-value is 005 when the 95 CI for RR does not include 10 or when 95 CI for MD does not include 0
1 Inclusion criteria
1 35 weeks or more gestational age
2 6 hours post birth
3 Any of the following
Metabolic or mixed acidosis with a pH of 70 or a base deficit 16 mmolL in an umbilical cord blood sample or any blood obtained within first hour after birth
10-minute Apgar score of 5
Ongoing resuscitation initiated at birth and continued for 10 minutes
4 Moderate to severe encephalopathy on clinical examination using a Thompson HIE score 7
5 Signed informed consent by parent
2 Exclusion criteria
1 Critical general condition
2 Aneuploidies 13 th 18 th 21 st
3 Birth weight 1800 g
4 Severe congenital defects with poor prognosis
5 Severe mechanical head injuries
6 Congenital malformations of digestive system esophageal atresia duodenal atresia gastroschisis omphalocele anal atresia
All eligible newborns will be randomized to one of the two groups
1 unfed during 72 hours of TH control group
2 fed group which will start receiving enteral feeding with mother milk or human donor breast milk at 10 mlkgday during first day of TH 20 mlkgday during second day and 30 mlkgday during third day experimental group
Both groups will be receiving parenteral nutrition PN from day one onwards Parenteral nutrition will be defined as receiving any type of nutrient solution in any volume through any route of administration peripheral venous cannula central venous catheter or umbilical catheter As the volume of enteral feeding will be increased the volume of PN will be decreased gradually
During the feeding process participants will be routinely checked up for the signs of feeding intolerance or NEC Feeding intolerance FI will be defined with the presence of one or more of these criteria 1 gastric residuals 50 on a single occasion among participants who received nosogastric feeds 2 biliousbloody gastric residuals among participants who received nosogastric feeds 3 abdominal distension increase in abdominal girth by 2 cm from baseline 4 emesis 5 gross or occult blood in the stool
Necrotizing enterocolitis NEC Bell stage 2 or 3 will be diagnosed based on the presence of one or more of the clinical signs bilious gastric aspirate or emesis abdominal distension occult or gross blood in stool and the presence of at least one of the following sonographic findings 1 pneumatosis intestinalis 2 portal vein gas andor 3 pneumoperitoneum
The criteria for stopping the trial intervention 1 any serious adverse events for enteral feeds mainly including NEC 2 infant developed severeunstable condition eg severe pulmonary hypertension which lead to stop TH and fasting must last for more than 24 hours
Primary endpoints 1 Combined Necrotizing enterocolitis or death Necrotizing enterocolitis will be defined by the modified Bells staging criteria stage II or stage III
2 Length of hospital stay assessed as duration of time spent in hospital before discharge measured in days
Secondary endpoints 1 Time to full enteral feeding full enteral feeding defined as participants receive all of their prescribed nutrition as milk feeds and do not receive any supplemental parenteral fluids or nutrition 2 Late-onset sepsis defined as sepsis occurring at or after 72 hours of life 3 Test of Infant Motor Performance scoring 4 MRI scoring using MRI scoring system by Rutherford et al classifying the severity of injury in the basal ganglia and thalami BGT cortex CX white matter WM each on a scale of 0-3 and posterior limb of the internal capsule PLIC scale 0-2 the higher number indicating more severe abnormality Total injury score TIS will be the sum of these regional scores scale of 0-11
5 MR spectroscopy parameters such as LacNAA LacCr NAACr CHONAA Primary outcomes are reduction of mortality or NEC stage 2 or 3 and length of hospital stay Investigators assumed that 50 difference as being a clinically significant Estimated that 43 children in each group are needed to achieve a significant difference with a power of 90 along with a two-sided 5 significance level Given the anticipated dropout rate of 20 52 subjects are necessary in each group
Participants will be randomly assigned to either control or experimental group with a 11 allocation based on a computer-generated randomization Redcap Caregivers of the participants will remain unblinded The researchers and the statistician will be blinded until the end of the study
The analyses will be performed after last patient out after monitoring and cleaning of data gathered from all patients Analyses will be performed by the investigators and statistician using the latest version of Medcalc statistics software
The flow of participants will be illustrated in a flow diagram according the Consolidation Standard of Reporting Trials CONSORT
The main analysis will be performed according the intention-to-treat ITT principle
The baseline characteristics of the included patients will be reported per randomization group and shown in a baseline table Dichotomous variables will be summarised as proportion of patients with the count divided by the total number of evaluated patients Continuous variables will be summarised as mean with standard deviation in case of normal distribution and as median with interquartile range in case of non-normal distribution Testing for normality of data distributions will be based on the Shapiro-Wilks test For continuous variables a footnote will state the number of evaluated patients Differences in baseline characteristics between study arms will be reported as preferred by the intended journal Differences between the study arms will be analysed using Fisher test independent t test or Mann-Whitney test if required by the journal
The assessment and analysis of the primary and secondary outcomes will be discussed separately All continuous data will be checked for normality For continuous outcomes the mean difference MD and for dichotomous outcomes the relative risk RR will be calculated The difference between study groups will be considered statistical significant when the p-value is 005 when the 95 CI for RR does not include 10 or when 95 CI for MD does not include 0
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None