Detecting Neonatal Hypoglycemia Using Real-Time Continuous Glucose Monitoring (CGM)
Phase: NA
Conditions: Neonatal Hypoglycemia
Sponsor: Stanford University

 
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Official Study Title:  Detecting Neonataal Hypoglycemia Using Real-Time Continuous Glucose 
Monitoring (CGM) 
 
NCT Number:  NCT03032523 
 
Date of Document:  3/6/2019 
 
 

 
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PROTOCOL 
 
TITLE 
 
Detecting Neonatal Hypoglycemia using Real-Time Continuous Glucose Monitoring (CGM) 
 
SUMMARY 
 
Newborn infants have many complex physiological changes taking place that are difficult to anticipate.  
Infants born to mothers who have diabetes during their pregnancy are especially vulnerable to 
hypoglycemia.  Our study will evaluate blood sugar changes during the first few days of life and the utility 
of CGM systems to detect clinically significant hypoglycemia in infants.  This randomized, controlled 
single-blind trial will compare infants on CGM alone versus those using CGM who are remotely monitored 
by a physician through the Dexcom Share application.  The number of hypoglycemic events that are 
detected in each group will be compared.  For each time point that the unblinded CGM group has a low 
blood sugar level, it will be verified by standard heelstick (capillary) measures.  Finally, the sensitivity and 
specificity of detecting hypoglycemia in the infant will also be determined. 
 
INCLUSION CRITERIA 
 
- 
Participants must be born at 34 weeks gestation or later 
- 
Participants must be admitted Lucile Packard Children’s Hospital 
- 
Infants born at outside hospitals and transferred to LPCH will be eligible for the study 
- 
Mothers have a diagnosis of pre-gestational diabetes 
- 
Mothers with gestational diabetes have poorly controlled gestational diabetes defined as elevated 
Hemoglobin A1c (greater than 6%) during pregnancy or hyperglycemia based on home 
glucometer readings while pregnant.  This includes fasting or pre-prandial blood glucose values 
of greater than 100 mg/dl, post-prandial blood glucose values greater than 140mg/dl at 1 hour or 
greater than 120mg/dl at 2 hours consistently. 
- 
Any mothers who require insulin, metformin, or glucose lowering medications during gestation 
 
EXCLUSION CRITERIA 
 
- 
Infants <2,000g will be excluded from the study.  
- 
If infants receive Acetaminophen, sensor readings will not be included in the analysis for 6 hours 
after the medication is given because this medication may falsely raise the sensor’s glucose 
readings.  
- 
Infants will also be excluded if they have an anomaly of the skin or subcutaneous tissue that 
would prevent proper adhesion, placement, and function of the sensor. 
- 
If at any point in time the infant must undergo MRI, CT scan, or diathermy treatment, the sensor, 
receiver, and transmitter will be removed from the patient completely. 
 
ENROLLMENT PROCEDURES: 
 
- 
Flyers advertising the study will be posted at the obstetrics clinics at Stanford University. 
- 
Parents of potential participants will be screened remotely for eligibility in the study. 
- 
Every effort will be made to ensure eligible mothers of participants will be recruited and 
consented by study team members prior to delivery. 
- 
Witnessed telephone consent may be obtained if the family is unable to meet in person. 
- 
The general study, risks, and benefits will be discussed with all potential participants’ legal 
guardians prior to enrollment 
 
 
STARTING THE DEXCOM CGM:  Application 
 

 
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- 
Participants enrolled in the study will be followed remotely to determine time of delivery of the 
infant (study participant).  
- 
A trained study team member or staff member will contact the attending physician on call for the 
newborn to let them know that the participant is enrolled in the study. 
- 
The trained study team member or staff member will come to the infant’s bedside and place the 
Dexcom sensor according to the following steps. 
- 
A Dexcom G4 CGM sensor (Dexcom, San Diego, CA) will be applied using the following steps.  
- 
After using Standard Precautions, a trained staff member will examine the skin for possible 
sensor sites. 
- 
An appropriate area of healthy, in-tact skin will be cleansed and allowed to dry.  The sensor 
will be subcutaneously inserted by trained staff according to the Dexcom user’s manual.  
- 
The transmitter will then be fastened on top of the sensor.  The blinded receiver will be kept 
near the patient to ensure a proper signal as much as possible during the study period. 
- 
In the remote monitoring group, Dexcom receivers will be blinded to the clinical staff directly 
caring for the patient by blinding the device using Dexcom Studio.  After blinding the receiver, 
it will be connected to an Ipod that will connect to the Stanford internet.  Using the Dexcom 
Share application installed on the Ipod, the blinded receiver will send glucose data to the Ipod 
which will remain locked and inaccessible to clinical staff during the study period.  The 
Dexcom Share application will send information to the study physician through the Dexcom 
Follow application on the study physician’s encrypted phone to allow remote monitoring of 
patients in the experimental group. 
- 
Using the Dexcom Follow Application, auditory and vibratory alerts will be enabled for blood 
glucose values <46 mg/dl or signal loss for >60 minutes and sent directly to the study 
physician remotely monitoring participants. 
- 
Signal loss of greater than 3 hours will require participants to have a new subcutaneous 
sensor inserted and the initial calibration steps will need to be repeated. 
- 
Dexcom Receivers and Ipods will remain connected to a power source as much as possible 
during the study period.   
 
DEXCOM CGM PROTOCOL: Calibration 
 
- 
After the initial 2 hour start-up period, the sensor will be calibrated using two successive capillary 
blood glucose measurements using a study glucometer. 
- 
The same type of device will be used for all capillary blood glucose measurements performed on 
the infant. 
- 
For each capillary blood glucose sample, an area of skin will be cleansed, allowed to dry, pricked 
using a sterile lancet, and the smallest amount of blood possible will be used for proper testing.   
- 
Every effort will be made to ensure capillary blood glucose levels are checked at least every 12 
hours from the time of initial calibration until the time of discharge or 7 days of life, whichever 
comes first. 
- 
Glucose levels will be entered into the transmitter for calibration within 5 minutes of obtaining the 
glucose measurement. 
- 
In the remote monitoring group, a trained study staff member will work with nursing staff to 
perform and input the calibration measurements into the receiver. 
 
MONITORING FOR HYPOGLYCEMIA 
 
- 
When the monitoring physician receives an alert for a low glucose value <46 mg/dl, they will 
contact the nurse taking care of the patient.  First, the infant will be assessed to see if excess 
pressure is being placed on the sensor due to positioning.  If so, the infant may be repositioned 
and monitored to see if the glucose values rise above 45mg/dl.  If CGM glucose values remain 
low, a bedside glucose reading will be performed. This value will be recorded in the chart and by 
the monitoring physician in the study.  Based on the standard of care blood glucose reading, the 
staff will take appropriate measures based on the standard of care (see appendix). 
- 
If the hypoglycemia alarm continues for an additional 60 minutes, the nurse caring for the patient 
will be prompted to obtain an additional standard of care blood glucose measurement. 

 
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If the measurement at 60 minutes shows that the patient has a BG >45mg/dl, the CGM 
may be re-calibrated (see below). 
- 
In the case of severe hypoglycemia (BG <35mg/dl) found in both control and experimental groups 
during routine calibration procedures will require that the clinical staff caring for the patient be 
notified to ensure safety of the patient. 
- 
For all blood glucose measurements that are >20% different from the Dexcom CGM values in the 
experimental group, a blood glucose test may be performed to re-calibrate the sensor prior to the 
12 hours.  Sensor re-calibration will only occur between glucose values of 40 mg/dl and 400 
mg/dl based on manufacturer guidelines. 
 
MONITORING FOR SENSOR SITES FOR INFECTION 
 
- 
Sensor sites will be assessed at least once per 12 hour nursing shift and as needed during 
nursing cares for the duration of the study.   
- 
Evidence of inflammation (redness, swelling, discharge) will be documented and discussed with 
the clinical care and research team.   
- 
If the sensor site is thought to be infected, the sensor will be removed immediately and 
appropriate steps will be taken to treat the infection by the clinical team managing the patient. 
 
RISKS ASSOCIATED WITH CGM USE 
When the needle and sensor are inserted, the child should expect to experience a small amount of pain for 
a few seconds.  After insertion, your child may or may not feel some tenderness or pain. 
  
Pain, inflammation or redness, swelling, minor infection, and minor bleeding at the sensor insertion site are 
possible risks with your child’s use of the study device.  In extremely rare cases an infection might spread 
to other parts of the body.  Significant or serious health risks with the investigational device are not 
anticipated. 
  
Minor irritation may occur where the adhesive pad is placed.  This will occur in most research participants 
and should clear up within hours to not more than a week after removal.  The child may experience some 
itching in the area during the healing process, which is normal.  The child may develop an allergic reaction 
to one or more parts of the sensor and transmitter.  This is similar to allergies that occur due to medical 
tape or jewelry.  Allergic reactions will usually be mild and require only a skin cream to make them 
better.  Severe allergic reactions are rare.  If the child has an allergic reaction, study staff should be notified. 
  
On rare occasion, the sensor may cause skin injury and tissue trauma known as medical adhesive-related 
skin injury (MARSI).  If this happens, study staff should be notified as soon as possible. 
  
There is a chance that the sensor or needle may break during use of the device.  This is not expected to 
occur; but, if it does, the study staff should be contacted about what to do. They will see if the child has 
symptoms of infection or inflammation, swelling, redness, or pain at the insertion site. Treatment will be 
provided if needed.  If a sensor breaks, it may be left under the skin indefinitely as long as no portion of the 
wire sensor fragment is visible above the skin and there are no symptoms of infection, redness, and/or 
swelling. 
  
The radio waves that the transmitter puts out will not hurt the family or their child, nor will the child be aware 
of them. 
 
EVALUATION AND TREATMENT OF HYPOGLYCEMIA 
 
- 
Clinical signs of hypoglycemia will be monitored and documented. 
- 
Hypoglycemic events will be treated using the existing treatment protocol (appendix) and will only 
be based upon glucometer values 
 
CONTACTING DEXCOM 

 
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Dexcom Technical Support information will be distributed to study personnel and contacted as 
needed.  The contact information is as follows:  1-877-339-2664 and 1-858-200-0200. 
 
 
DEXCOM CGM REMOVAL 
 
- 
The CGM will remain in place for 7 days or until the patient is discharged. 
- 
If it is thought that additional value would be gained from continuing use of the CGM for clinical 
care after 7 days, the CGM may be continued in an unblinded fashion, however the data collected 
will not be used for the purposes of the study.   
- 
If the sensor should become dislodged at any time during the study period, it will be replaced 
using the same protocol.  However, a new area of healthy skin will be chosen for sensor 
placement. 
- 
At the end of the study time period, the sensor will be carefully removed by trained staff. 
- 
Skin will be examined carefully and any changes to the skin associated with sensor use will be 
documented. 
 
DATA ANALYSIS 
 
Data collection 
Maternal data, including mother’s age, pregnancy history, type of diabetes, and treatment of diabetes 
during pregnancy were collected. Neonatal characteristics collected included sex, race, ethnicity, 
gestational age, birth weight, type of delivery, and other risk factors for hypoglycemia. Perinatal stressors 
were defined as an Apgar score <7, admission to NICU, or treatment of the infant beyond the usual 
suctioning and stimulating that routinely occurs after birth.14 Prematurity was defined as birth at <37 
weeks gestation. Small for gestational age (SGA) infants weighed less than the 10th percentile for 
gestational age, whereas large for gestational age (LGA) infants weighed greater than the 90th percentile 
for gestational age. 
 
Power calculation 
Using an older retrospective CGM device in a similar cohort of at-risk infants, Harris found that using 
similar SOC intermittent heel-stick glucose monitoring, 32% of infants had glucose levels <47 mg/dL.15 
We estimated that in our cohort, the SOC would find 32% of these high-risk infants with glucose levels 
<47 mg/dL. We estimated that with a sample size of 40, we should be able to detect a higher CGM rate of 
hypoglycemia of *57% (80% power, alpha = 0.05, one sided). However, because we were unable to 
recruit 40 infants during the time frame of the randomized trial, we modified the study design; instead, our 
goal was to determine if there was additional benefit of using CGM monitoring to detect hypoglycemia 
missed by SOC testing and to determine the false-positive rate of CGM alerts for hypoglycemia. 
 
Outcome measures 
Hypoglycemia was defined as a glucose concentration of <45mg/dL in order to correspond with the 
hospital’s SOC protocol. Primary outcome measures were the number of hypoglycemic events detected 
by the sensor that were not detected by the hospital SOC. Secondary outcome measures were 
sensitivity, specificity, and positive predictive value of the device to detect hypoglycemia. When 
evaluating number of hypoglycemic episodes that occurred with each infant, the start of each 
hypoglycemic episode needed to be at least 60 minutes from the last episode to allow for treatment and 
resolution of hypoglycemia. A duration of 60 minutes was used to allow time for breast feeding in 
accordance with the nursery’s SOC procedures (Supplementary Fig. S1). The CGM data were reviewed 
post hoc using Dexcom Studio Software. Using the Dexcom Studio Software to calculate the average 
CGM glucose level for each infant, a value of 39 mg/dL was used for all values that were reported as 
‘‘low.’’ All values reported by the CGM as ‘‘low’’ were excluded from the accuracy analysis. The mean 
absolute relative difference (MARD) was calculated by taking the absolute value of the difference 
between the CGM and hospital glucometer values and dividing by the hospital glucometer value 
individually, and then taking the mean of these values. 
 

 
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Additional outcome measures included CGM feasibility in the hospital setting. During the recruitment 
process and throughout the study, we asked caregivers for feedback about satisfaction with the CGM 
device. If any devices were removed before the end of the study period, we requested feedback from the 
families as well. 
 
DATA COLLECTION SCHEDULE 
 
Measurement 
Study Entry 
Daily 
End of Study 
Demographics 
X 
 
 
Medical History (mother) 
X 
 
X 
Medical History (infant) 
X 
 
X 
Chart Review 
 
X 
X 
Adverse Events 
 
X 
X 
Nutrition 
 
X 
X 
Glycemic Trends 
 
X 
X 
Exam of skin site/sensor site 
X 
X 
X 
 
 
 

 
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APPENDIX: