Neurodevelopmental outcome after neonatal hypoglycaemia: a multi-centre randomised controlled trial comparing intensive treatment versus expectant glucose monitoring in 'high risk' newborns

ISRCTN	ISRCTN79705768
DOI	https://doi.org/10.1186/ISRCTN79705768
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	ZonMW Doelmatigheid 80-007022-98-07406
Sponsor	Academic Medical Centre (AMC) (The Netherlands)
Funder	The Netherlands Organisation for Health Research and Development (ZonMw) (The Netherlands)

Submission date: 23/08/2007
Registration date: 23/08/2007
Last edited: 06/02/2020

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Pregnancy and Childbirth

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Ms Debbie Nuytemans
Scientific

Department of Neonatology
Emma Children's Hospital
Academic Medical Centre (AMC)
P.O. Box 22660
Amsterdam
1100 DD
Netherlands

Phone	+31 (0)20 566 3477
Email	HYPO-EXIT@AMC.nl

Study information

Primary study design	Interventional
Study design	Multicentre, randomised, single-blinded, active controlled, parallel group trial
Secondary study design	Randomised controlled trial
Scientific title	Neurodevelopmental outcome after neonatal hypoglycaemia: a multi-centre randomised controlled trial comparing intensive treatment versus expectant glucose monitoring in 'high risk' newborns
Study acronym	HYPO-EXIT
Study objectives	Current clinical practice varies widely, especially for infants with 'moderate' hypoglycaemia, due to lack of methodological sound studies. This leads to both over- and under-treatment of hypoglycaemic infants. This study-protocol is directed at the comparison of two accepted management strategies at both ends of the current treatment-spectrum of moderate hypoglycaemia in 'high risk' newborns: an intensive treatment versus an expectant monitoring strategy.
Ethics approval(s)	Ethics approval received from the local medical ethics committee
Health condition(s) or problem(s) studied	Developmental-disabilities, blood-glucose, hypoglycaemia
Intervention	In the intensive treatment arm the aim is to increase the glucose concentration above 2.5 mmol/l within three hours by increasing the carbohydrate intake by oral nutrition and/or intravenous glucose administration. In the expectant arm the aim is to maintain the glucose concentration above 2.0 mmol/l by the usual oral nutrition protocol.
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Glucose
Primary outcome measure(s)	Primary outcome is neurodevelopment at 18 months, assessed with the Bayley Scales of Infant Development.
Key secondary outcome measure(s)	Current secondary outcome measures as of 04/09/2019: 1. Costs for medical treatment and hospital admission until 18 months of age: 1.1 costs for diagnostic tests and treatment of the infant (glucose measurements, supplemental feeding, tube-feeding, intravenous glucose administration), and hospitalization costs for both the infant and mother 1.2 costs for medical consumption related to neurodevelopmental impairment until the age of 18 months (visits to healthcare professionals and hospital admission after the neonatal period) 2. Plasma glucose concentrations and carbohydrate intake (breastfeeding, oral or enteral feeding and intravenous glucose) 3. Frequency of treatment failure, defined as infants who become severely hypoglycaemic despite the treatment they received (frequency and severity of hypoglycaemia episodes after randomization). Previous secondary outcome measures: Secondary outcomes are costs for medical treatment and hospital admission until 18 months of age.
Completion date	01/04/2013

Eligibility

Participant type(s)	Patient
Age group	Neonate
Sex	All
Target sample size at registration	800
Total final enrolment	689
Key inclusion criteria	Current participant inclusion criteria as 04/09/2019: Infants greater than or equal to 35 weeks gestational age and greater than or equal to 2000 g with one of the four major risk factors for neonatal hypoglycaemia: 1. Small-for-Gestational-Age infants (SGA, birth-weight-for-gestational-age less than P10) 2. Large-for-Gestational-Age infants (LGA, birth-weight-for-gestational-age greater than P90) 3. Near-term infants 35 0/7 to 36 6/7 weeks gestational age with a birth weight greater than 2000 g 4. Infants of Diabetic Mothers (IDM) Birth-weight-for-gestational-age is defined according to the growth charts of the Perinatale Registratie Nederland (PRN). Previous participant inclusion criteria: Infants greater than or equal to 35 weeks gestational age and greater than or equal to 2000 g with one of the four major risk factors for neonatal hypoglycaemia: 1. Small-for-Gestational-Age infants (SGA, birth-weight-for-gestational-age less than P10) 2. Large-for-Gestational-Age infants (LGA, birth-weight-for-gestational-age greater than P90) 3. Near-term infants 35 0/7 to 36 6/7 weeks gestational age with a birth weight greater than 2000 g 4. Infants of Diabetic Mothers (IDM) Birth-weight-for-gestational-age is defined according to the Kloosterman growth charts.
Key exclusion criteria	Current participant exclusion criteria: Infants with serious co-morbidity will be excluded, because their co-morbidity can also affect neurodevelopment: 1. Very preterm infants (less than 34 6/7 weeks gestational age) 2. Severe perinatal asphyxia - presence of at least three of the next criteria: 2.1. Signs of intrauterine asphyxia, like late decelerations on Cardiotocogram (CTG) or meconium stained amniotic fluid 2.2. Arterial umbilical cord pH less than 7.10 2.3. Delayed initiation of spontaneous respirations greater than 5 minutes after birth 2.4. Five minute Apgar score less than 5 2.5. Multi-organ failure 3. Severe perinatal infection: requiring support of vital functions (infants without clinical signs of infection who are treated with antibiotics because of suspected perinatal infection can be included) 4. Respiratory insufficiency requiring respiratory support 5. Severe hypotension requiring vasopressor support 6. (Strong suspicion of) a syndrome or major congenital malformations Other exclusion criteria: 7. Intravenous glucose administration before randomization 8. (Strong suspicion of) inborn error of metabolism 9. (Strong suspicion of) hyperinsulinism, except infants of diabetic mothers 10. No informed consent Previous participant exclusion criteria: Infants with serious co-morbidity will be excluded, because their co-morbidity can also affect neurodevelopment: 1. Very preterm infants (less than 34 6/7 weeks gestational age) 2. Severe perinatal asphyxia - presence of at least three of the next criteria: 2.1. Signs of intrauterine asphyxia, like late decelerations on Cardiotocogram (CTG) or meconium stained amniotic fluid 2.2. Arterial umbilical cord pH less than 7.10 2.3. Delayed initiation of spontaneous respirations greater than 5 minutes after birth 2.4. Five minute Apgar score less than 5 2.5. Multi-organ failure 3. Severe perinatal infection: requiring support of vital functions (infants without clinical signs of infection who are treated with antibiotics because of suspected perinatal infection can be included) 4. Respiratory insufficiency requiring respiratory support 5. Severe hypotension requiring vasopressor support 6. (Strong suspicion of) a syndrome or major congenital malformations Other exclusion criteria: 7. (Strong suspicion of) inborn error of metabolism 8. (Strong suspicion of) hyperinsulinism, except infants of diabetic mothers 9. No informed consent
Date of first enrolment	01/10/2007
Date of final enrolment	01/04/2011

Locations

Countries of recruitment

Netherlands

Study participating centre

Department of Neonatology

Amsterdam
1100 DD
Netherlands

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	06/02/2020	06/02/2020	Yes	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

06/02/2020: The following changes were made to the trial record:
1. Publication reference added.
2. The total final enrolment was added.
04/09/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/10/2010 to 01/04/2011.
2. The overall end date was changed from 01/10/2010 to 01/04/2013.
3. The secondary outcome measures were changed.
4. The inclusion criteria were changed.
5. The exclusion criteria were changed.