Clinical trial NCT04353713: Gel for Early Hypoglycaemia Prevention in Preterm Infants
Official title: Oral Dextrose Gel to Prevent Early Hypoglycaemia in Very Preterm Infants
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hypoglycemia in Newborn Infants
Keywords: Prematurity
oral dextrose gel
randomized controlled trial
placebo
Lead sponsor: University College Dublin
Sponsor class: OTHER
First posted: 2020-04-20
Enrollment: 534
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a randomised, double-blinded (using masking), placebo controlled clinical trial. It will involve multiple study sites.

The study population will consist of infants born at ≤32 weeks gestation. These may include singleton or multiples births.

Randomisation will be stratified into two groups using gestational age at birth:

≤29 weeks

29+1 to ≤32 weeks

Randomisation will also be stratified by multi-centre site.
Primary purpose: PREVENTION

Brief summary: The GEHPPI study is a multicentre placebo controlled randomized controlled trial that aims to prevent early hypoglycaemia in preterm newborns born at ≤32 week's gestation. To do this we will prophylactically administer to these newborns either a small amount of dextrose 40% gel early as possible after birth via the buccal route in the delivery room or a placebo. We hope this dextrose gel will prevent hypoglycemia occurring during the time period needed for the newborns to be transported to the neonatal unit where they will have their venous access inserted.

This trial aims to demonstrate that administering dextrose gel via the buccal route is a simple and rapid method of preventing early hypoglycaemia in this vulnerable patient group.

This trial aims to show that giving dextrose gel via the buccal route is simple and feasible in this premature population.

This trial aims to reduce the need for rescue intravenous dextrose (2ml/kg dextrose 10%) in those babies who are hypoglycaemic at the time of obtaining intravenous access.

Detailed description: Fetal glucose homeostasis in-utero has some very important characteristics: Kalhan et al. showed that from 20 weeks gestation onwards the lower limit for in-utero (foetal) glucose was 3 mmol/L over most of their remaining gestation (Kalhan et al., 1979); Secondly, foetal glucose control in-utero is completely dependent on maternal plasma glucose control and maternal insulin secretion (Stanley et al., 2015); Lastly, steady state glucose utilization rates in term neonates are 4 to 6 mg/min/kg, however at earlier gestational ages (both foetal and preterm infants) these values are higher 8-9 mg/min/kg (Hay, 2006) indicating that preterm infants need an early and reliable glucose source at birth.

A local retrospective audit in our Level 3 Neonatal Unit (King et al., 2018) reviewed 90 patients who were born in-house ≤ 32 weeks gestation with birth weight ≤1500g over 12months in CWIUH (April 2016 - March 2017). Analysis showed that the first blood gas (at the time of first intravenous insertion) was at median 48mins (IQR 15min) life. Data showed that 30 of 90 patients (33.3%) had hypoglycaemia of \<1.8 mmol/L at the time of first intravenous access. This hypoglycaemia is at a level below an operational threshold (level at which to intervene) most commonly accepted internationally.

Recommendations from the Pediatric Endocrine Society (2015) are that for high-risk neonates (without a suspected congenital hypoglycaemia disorder), the goal of treatment is to maintain a plasma glucose concentration \>2.8 mmol/L for those aged \< 48hrs (grade 2+ evidence) (Thornton et al., 2015). However the American Academy of Pediatrics Committee on Fetus and Newborn advise that if asymptomatic, intravenous treatment of hypoglycaemia is not needed until glucose concentrations are \< 1.4 mmol/L (within 4hrs after birth) or \<2.0 mmol/L (from 4 to 24 h after birth) (Adamkin, 2011). However if symptomatic and blood glucose \<2.2 mmol/L they recommend treating immediately (Adamkin, 2011).

Regarding long-term outcomes, in 2006 Boluyt et al. performed the first systematic review of the evidence for neurodevelopmental impairment following hypoglycaemia in the first week of life. They felt that none of the 18 eligible studies identified provided a valid estimate of the effect of neonatal hypoglycaemia on neurodevelopment. The authors provided recommendations about an optimal study design (Boluyt et al., 2006). In 2018 Shah et al. performed a systematic review and meta-analysis which included neonates born ≥32 weeks gestation who had been screened for hypoglycaemia in the 1st week of life. The authors felt that tests of general development in infancy are unlikely to adequately assess the effects of neonatal hypoglycaemia on brain development, but instead future studies will require longer-term end points at least into mid-childhood, including specific tests of visual-motor and executive function (Shah et al., 2018).

Despite the absence of consensus in the medical literature today, this study's investigators feel that tackling the problem of early hypoglycaemia in these very/extremely premature infants will allow a smoother transition from in-utero (foetal) to postnatal (ex-utero) glucose homeostasis. This may have important long-term neurodevelopmental consequences.

Our study aims to tackle this problem of early hypoglycemia in these vulnerable newborns. To do this we will give these newborns a small amount of 40% dextrose gel as early as possible after birth via the buccal route. They will absorb the gel through the small blood vessels located on the inside of their cheeks \& gums and it will enter their bloodstream quickly. We hope this gel will prevent hypoglycemia occurring during the time period needed for the newborns to be transported to the neonatal unit where they will have some form of venous access inserted.

As this research is a trial we want to see if this dextrose gel has this beneficial effect or not. To do this we need to compare the dextrose gel to a non-sugar containing gel (called the "placebo"). The placebo gel will contain simple cellulose ingredient but does not contain sugar and will have no effect on blood glucose. Both gels used in the trial will look identical in appearance and neither the researcher nor the patient (nor parent/s) will know whether they received either the dextrose or the placebo gels. Which gel a newborn receives will be assigned at random, immediately prior to the birth. All newborns will be cared for in the same way according to best standard care.

Newborns will not undergo any additional tests as part of the study. Blood glucose levels will be measured as per standard practice at the time vascular access is obtained. Blood glucose values will be measured on either a blood gas analyzer or laboratory glucose. Patient data collected as part of the study will be pseudo-anonymized/ anonymized and stored safely. Consent for participation can be withdrawn at any time.

Eligibility criteria: Inclusion Criteria:

* The study population will consist of infants born at ≤ 32 weeks gestation. These may include singleton or multiples births.

Exclusion Criteria:

* Any newborn where comfort care (palliative approach) is planned for the care of the newborn following delivery. This will often be due to an antenatally diagnosed lethal and/or major congenital anomaly.

Primary outcomes:
measure: Proportion of newborns with initial hypoglycemia after birth
timeFrame: 30-60 minutes after birth
Secondary outcomes:
measure: Proportion of newborns with a hypoglycaemia episode < 2.6mmol/L (46 mg/dl) within first 24hrs after birth
timeFrame: 24 hours after birth
measure: Proportion of newborns with a hypoglycaemia episode <1.8mmol/L (32.4 mg/dl) within first 24hrs after birth
timeFrame: 24 hours after birth
measure: Number of episodes of hypoglycaemia <2.6mmol/L (46 mg/dl) within first 24hrs after birth
timeFrame: 24 hours after birth
measure: Proportion of newborns with a hyperglycaemia episode > 10 mmol/L (180 mg/dl) within first 24hrs after birth
timeFrame: 24 hours after birth
measure: Proportion of newborns who received rescue IV dextrose within first 24hrs after birth
timeFrame: 24 hours after birth
measure: Tolerance of buccal gel in delivery room
timeFrame: 30 minutes after birth
measure: Incidence of symptomatic hypoglycaemia
timeFrame: 24 hours after birth
measure: Proportion of newborns who died within the first 12 hours after birth
timeFrame: 12 hours after birth
measure: Proportion of newborns who died after 12 hours following birth but prior to discharge home
timeFrame: 6 months
measure: Incidence of early bacterial sepsis and/or meningitis
timeFrame: First 3 days after birth
measure: Incidence of necrotising enterocolitis (NEC).
timeFrame: 6 months
measure: Proportion of newborns with severe retinopathy of prematurity requiring treatment.
timeFrame: 6 months
measure: Proportion of newborns with severe (grade III/IV) intraventricular-germinal matrix hemorrhage (IVH-GMH).
timeFrame: 6 months
measure: Proportion of newborns with periventricular leukomalacia (PVL).
timeFrame: 6 months
Other outcomes:
Locations:
city: Praha
country: Czechia
facility: University Hospital Motol
city: Dublin
country: Ireland
facility: Rotunda Hospital
city: Dublin
country: Ireland
facility: The National Maternity Hospital
city: Dublin
country: Ireland
facility: Coombe Women & Infants University Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
Study officials:
affiliation: Coombe Women & Infants University Hospital
name: John P Kelleher, MB BCH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Committee on Fetus and Newborn; Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011 Mar;127(3):575-9. doi: 10.1542/peds.2010-3851. Epub 2011 Feb 28.
citation: Boluyt N, van Kempen A, Offringa M. Neurodevelopment after neonatal hypoglycemia: a systematic review and design of an optimal future study. Pediatrics. 2006 Jun;117(6):2231-43. doi: 10.1542/peds.2005-1919.
citation: Hay WW Jr. Recent observations on the regulation of fetal metabolism by glucose. J Physiol. 2006 Apr 1;572(Pt 1):17-24. doi: 10.1113/jphysiol.2006.105072. Epub 2006 Feb 2.
citation: Kalhan SC, D'Angelo LJ, Savin SM, Adam PA. Glucose production in pregnant women at term gestation. Sources of glucose for human fetus. J Clin Invest. 1979 Mar;63(3):388-94. doi: 10.1172/JCI109314.
citation: Shah R, Harding J, Brown J, McKinlay C. Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis. Neonatology. 2019;115(2):116-126. doi: 10.1159/000492859. Epub 2018 Nov 8.
citation: Stanley CA, Rozance PJ, Thornton PS, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Simmons RA, Sperling MA, Weinstein DA, White NH, Wolfsdorf JI. Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. J Pediatr. 2015 Jun;166(6):1520-5.e1. doi: 10.1016/j.jpeds.2015.02.045. Epub 2015 Mar 25. No abstract available.
citation: Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sperling MA, Weinstein DA, White NH, Wolfsdorf JI; Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015 Aug;167(2):238-45. doi: 10.1016/j.jpeds.2015.03.057. Epub 2015 May 6. No abstract available.