Continuous Glucose Monitoring and Preterm Infants

Background - Neonatal hypoglycemia is a common event during the first week of life and has
been associated to brain injuries and poor neurodevelopment. Unfortunately it may be
unrecognized for several hours from its occurrence, since it is asymptomatic/poor symptomatic
in newborns (Hay WW, 2009; Cornblath, 2000; Adamkin DH, 2011; Burns et al, 2008; Wong, 2013;
Duvanel et al, 1999) Despite the dramatic consequences of prolonged hypoglycemia on the
neonatal brain are well known, the only tool to recognize it is represented by the capillary
glycemic test performed according to risk-based protocols of Neonatal Intensive Care Units
(NICUs): they consider a limited window of intervention based on 2-3 glycemic tests a day
(Thomas F et al, J. Diab Science Technol. 2014).

Continuous glucose monitoring systems have offered, in the last decade, a new powerful tool
to recognize more hypoglycemic events in neonates than traditional monitoring. All the works
developed in neonates, to date, have been aimed to evaluate the performance of the CGM
devices and have been used to record the effect of medical "intervention" in the correction
of hypo or hyperglycemia (Neonatal Insulin Replacement Therapy in Europe (NIRTURE, Beardsall
et al, NEJM 2008; McKinlay et al, NEJM 2015) (Harris et al J Pediatrics, 2010; Beardsall et
al, Arch Dis Child Fetal Neonatal 2013). The CGM has never been used to drive medical
inteventions in newborns and evaluate as independent tool to improve time-in-target for
glycemia.

Previous studies demonstrated that up to 81% of the hypoglycemic episodes were not detected
with blood glucose measurement (Harris et al, J Pediatrics 2010). All the published studies
in neonates, to date, have used Medtronic CGM systems (Medtronic, USA). No adverse effects,
associated to the implant of CGM, have been reported neither in late-preterm neither in
preterm newborns.

Glycemic control in terms, and moreover, in preterm newborns still represent a challenge for
physicians and the wide fluctuation (both hyperglycemia and hypoglycemia) commonly observed
in such population still remains difficult to be managed with traditional blood glucose
monitoring (few data/day, delay of therapeutic intervention).

Aim - The study the Investigators are going to conduct is aimed to evaluate if CGM, as driver
of therapeutic decisions in preterm newborns (birthweight ≤1500g, gestational age ≤32 weeks)
during the first week of life, may be able to maintain "euglycemia". Euglycemia will be
defined as values within the range 72-144mg/dl (4-8mmol/L)(Harris et al J Pediatrics, 2010;
Beardsall et al, Arch Dis Child Fetal Neonatal Ed 2013)

Study design - Randomized Controlled Trial

- Patients: newborns with GA ≤32weeks and/or BW≤ 1500 g. They will be enrolled within the
first 48 hours of life

- Intevention group: Unblinded CGM (DexcomG4Platinum) data to adequate daily glucose
intake

- Control group: Blinded CGM with daily glucose intake adequated according to SMBG (=2
blood glucose/day)

- Primary Outcome: to evaluate if Unblinded CGM increases the time within "euglycemic"
range (72-144mg/dl)

Materials and Methods - Dexcom G4 Platinum (Dexcom Inc, CA - USA) sensor will be applied
within 48 hours from birth to the study population on the lateral side of thigh, after
parents' consent collection.

All the patients will be randomized to the blinded or unblinded group before the application
of CGM. Randomization will be performed using a randomization list electronically generated.

Unblinded group (intervention/open CGM group): they will wear CGM for 7 days, the alarms of
CGM will be switched on and the daily intake of carbohydrates will be adapted according to
CGM data. The study staff will record data every three hours in absence of hypo alarms (see
below for carbs adjustment procedure).

Blinded group: they will wear CGM for 7 days, the alarms and the CGM monitor will be blinded.
At least two calibrations a day, according to manufacturer instruction, will be inserted. The
daily amount of carbohydrates will be decided according to blood glucose test (at least
2/day) and to recommendation of American Academy of Pediatrics (see below).

Numerosity: the estimated numerosity is 50 patients according to primary outcome.
Unfortunately no data are available on this population; 10 extra patients will be recruited
in case of premature interruption of recording (due to sensor detachment, malfunction, loss
of the patient or interruption of monitoring due to local/systemic complication) in order to
ensure a total amount of 250 days of monitoring (50% in the UB-CGM group and 50% in the B-CGM
group) with a maximum amount of 350 days of monitoring. So the estimated time of monitoring
is expected to be min 250, max 350 days, divided into the two groups.

Reasons for study interruption: local and/or systemic complication due to the application of
device, transfer of patient to another center of care, withdrawal of consent, death,
malfunction of device. Reasons for interruption of monitoring will be specified in the final
report.

Carbohydrates adjustment procedure: the procedure for carbohydrates adjustment uses a
worksheet described in Agus MSD, Steil G et al NEJM 2012 and adapted to NICU standard of
nutrition suggested from American Academy of Pediatrics. The worksheet has been set up
according to the NICU protocols in agreement with recommendation of American Academy of
Pediatrics, Committee on Nutrition.

The 1st day intake is set on 6-8gr/kg of carbohydrates; a default daily increase of
1gr/kg/day in case of euglycemia is applied; such increase may variate according to the CGM
data in the unblinded group or to the 2 glycemic tests performed in the blinded group in
order to achieve the target as following:

i. if the average was >= 180 mg/dL decrease the calculated GIR by 1 g/kg/d ii. If the average
was between 144 and 179 mg/dL do not make any adjustment iii. If the average was between 72
and 143 mg/dL check if the minimum GIR has been reached and if not increase the value to the
minimum GIR for that day iv. If the average was lower than 72 mg/dL increase the rate to the
either the minimum rate + 2 or the calculated rate plus 2, whichever is bigger; v. if
glycemia <41mg/gl: increase of 2.8g/kg/die the GIR and perform a bolus of 2ml/kg/d of G10%.

Details of the worksheet have been described in Agus et al (NEJM2012).

Worksheet has been designed considering as follows:

Target 108,00 Low limit 72,00 High limit 144,00 Hyper Theshold 180,00 Hypo Threshold 40,00 A
decrease has been considered above hyper threshold of 1g/kg/d up to a minimum GIR of
4.5g/k/d. No increase will be performed between 144 and 180mg/dl.

Data analysis will be performed as intention to treat (ITT).

Discussion: perspective and limits - Euglycemia definition remains controversial in
neonatology. Even though, in our study, we have decided to adopt the NIRTURE targets
(Beardsall et al, 2010) considering optimal a range from 72 mg/dl (4 mmol/L) to 144mg/dl (8
mmol/L). Values below 40mg/dl will require a G10% bolus (2ml/kg) and an increase of 2.8gr/kg
of intake of carbs; values between 40 and 77mg/dl require an increase of carbs adapted to
reach the middle point of the expected target. Similarly for values above the upper limit we
have considered a decrease of carbs intake (minimum 4.5gr/kg/day).

The main difference between the two study groups is represented by the number of information
available for the physician and, consequently, from the number of changes in glucose intake.

The use of a worksheet will allow the investigators to avoid inter-individuals variability in
making infusion changes standardizing the interventions in two groups.

Actually the traditional system of monitoring of glycemia has been demonstrated to be unable
to detect a significant number of glycemic variations during the daytime. Increasing the
number of blood glycemic test (by heel prick) would mean to increase the number of painful
procedures for the newborn with an uncertain benefit and the workload of the staff.

Disclosures: Dexcom Inc, USA will provide materials for the study as donation to the Neonatal
Intensive Care Unit of University Hospital of Padua, Italy.

The study has been designed as a no-profit research project by the Principal Investigators
and Collaborators of Neonatal Intensive Care Unit of University of Padua, Department of
Bioengineering (University of Padua) and Boston Children's Hospital.

Dexcom Inc has not been involved in the study design and will not be involved in results
evaluation.

Inclusion Criteria (and/or):

- <= 32 weeks gestation

- birthweight <1500 g

Exclusion Criteria:

- birthweight <500g

- malformative syndrome

- lack of parental consent

- chromosomal abnormalities