Hormone Responses During Hypoglycemia and the Accuracy of Continuous Glucose Monitors
Condition: Type 1 Diabetes
MeSH terms: Hypoglycemia
Study type: Observational

Summary: 
      The primary objective of this study will be to compare the glucose level at which
      counter-regulatory hormone responses occur during hypoglycemia in young children with
      diabetes, with the glucose level counter regulatory hormone responses that occur in older
      children with diabetes.
    

Detailed description: 
      The present study is being undertaken to compare counterregulatory hormone responses to a
      mild and gradual reduction in plasma glucose in young children with T1DM versus responses in
      adolescents. The studies will be performed under the close supervision of the professional
      staff of each DirecNet center and frequent bedside monitoring of plasma glucose
      concentrations will ensure that clinically significant hypoglycemia is prevented from
      developing. All subjects will be admitted to the CRC and have an IV line for blood sampling
      inserted on the evening prior to study to reduce stress on the morning of the study. The
      study procedure will be simplified and made less invasive in comparison to a clamp or
      standard insulin infusion study (i.e. only the one IV for blood sampling will be needed) by
      limiting enrollment to insulin pump-treated subjects who will have their basal rates modestly
      increased to produce the hypoglycemic stimulus. Monsod and colleagues used the same procedure
      of increasing the basal insulin infusion dose to induce a gradual fall in plasma glucose in
      youth with type 1 diabetes in a study that compared the ability of injections of glucagon and
      epinephrine to treat mild hypoglycemia. It is particularly important to note that once the
      blood glucose level falls below 60 mg/dl, a blood sample will be obtained and hypoglycemia
      will then be immediately corrected by intravenous administration of exogenous glucose. In our
      recent DirecNet study, ~25% of children and adolescents had plasma glucose levels below 60
      mg/dl during a typical night and this rose to ~50% of subjects when there was antecedent
      exercise in the late afternoon. Moreover, the frequency of mild as well as severe
      hypoglycemia is substantially higher in pre-school children than in children and adolescents.
      This safe and rigorously designed study will provide important new information regarding the
      role of inadequate counter-regulation on the increased risk of hypoglycemia in very young
      children with T1DM.

      Real-time continuous glucose sensing systems offer the potential to markedly lower the risk
      of hypoglycemia in youth with T1DM. However, the DirecNet inpatient accuracy study
      demonstrated that the first generation of these devices was inaccurate when blood glucose was
      lowered to less than 70 mg/dl. In that study, children with T1DM between 3-17 years of age
      were admitted to the CRC for approximately 26 hours during which they wore 1-2 Medtronic
      MiniMed CGMS and 1-2 Cygnus GlucoWatch G2 Biographer continuous glucose monitors. In every
      subject in that study, blood samples were obtained every 30-60 minutes from an indwelling
      intravenous catheter for measurement of reference plasma glucose levels in the DirecNet
      Central Laboratory. The Guardian-RT continuous glucose monitoring systems is a real-time
      continuous glucose monitor that has considerable promise for use in children with diabetes.
      Therefore, a secondary aim of this study is to obtain very important data regarding the
      accuracy of this system during hypoglycemia in young children, as well as adolescents.

      The Guardian-RT has been approved by the FDA for detecting trends and tracking patterns in
      adults (18 and older) and are indicated for adjunctive rather than replacement of standard
      home glucose monitoring devices. The sensor has been approved by the FDA for use for up to 72
      hours but can function for a longer period of time.

      The primary objective of this study will be to compare the glucose level at which
      counter-regulatory hormone responses occur during hypoglycemia in young children with
      diabetes, with the glucose level counter regulatory hormone responses that occur in older
      children with diabetes. We hypothesize that the children in the younger age group will not
      have a counterregulatory response until a lower glucose level is reached compared with
      children in the older age group.

      Secondary objectives will be:

        1. To assess signs and symptoms at different glucose levels of hypoglycemia in younger
           children and compare those with the older children. Furthermore, symptoms will be
           compared to counter regulatory hormone levels in the two age groups. Symptoms will be
           assessed using physiologic data and using an age-appropriate questionnaire that would be
           completed during the test by the subject (where appropriate) and by a parent.

        2. To assess whether there is a difference in counter-regulatory hormone response in each
           age group, among those who had at least 2-3 episodes of hypoglycemia per day or night
           prior to the study compared with those who had an occasional or no episodes of
           hypoglycemia prior to the test. Subjects will wear a Guardian RT for 6 days (+1 day)
           prior to the test to assess episodes of hypoglycemia.

        3. To examine the accuracy of the Guardian-RT during hypoglycemia in children with type 1
           diabetes.

      Beginning the Study

      When a child enters the study, the following will be done:

        1. Informed consent is obtained from eligible subjects (age 3 to <7 or 12 to <18 years, T1D
           for >1 year, insulin pump being used).

        2. On the day of enrollment a hemoglobin A1c is obtained and instructions are given for use
           of the Guardian RT. The study personnel will supervise the subject or parent inserting
           the sensor in the clinic. The subject will be instructed to complete at least four
           glucose measurements a day using the study HGM. Instructions will also be given for
           response to Guardian RT alarms prior to the CRC admission.

        3. The subject will return for an 18-hour overnight CRC admission approximately 6 days (+ 1
           day) after the enrollment visit.

             -  Subjects will continue using the Guardian RT sensor inserted prior to the
                admission.

             -  For subjects of sufficient size to accommodate additional devices, a second
                Guardian-RT sensor will be inserted. An intravenous catheter will be inserted for
                reference measurements (glucose, epinephrine, norepinephrine, cortisol, glucagon
                and GH), which will be drawn during the subcutaneous insulin infusion test the
                following morning to send to a central laboratory.

             -  For subjects of sufficient weight (subjects >14.9kg at reinfusion centers and
                >26.3kg at discard centers) to accommodate the volume of blood required, blood
                glucose measurements will be made every 30 minutes during the admission to allow
                for assessment of the accuracy of the Guardian-RT.

             -  For subjects of sufficient weight to accommodate the volume of blood required,
                blood glucose measurements will be made every 15 minutes for two hours after
                dinner. This will allow for assessment of the accuracy of the Guardian-RT in
                detecting change during a period of rising blood glucose.

             -  At approximately 8:00 a.m. the subcutaneous insulin infusion test will start.

                  -  Prior to starting the test, a HypoMon® may be placed around the subject's
                     chest using an adjustable strap.

                  -  The glucose concentration as measured by the study HGM must be >110 mg/dL to
                     start the test.

                  -  At the start of the test, the basal insulin rate will be increased by
                     approximately 25-50% to provide a gradual decline in blood glucose. A small
                     priming bolus dose of insulin equal to approximately one hour of the subject's
                     usual basal dose may also be given at the discretion of the investigator in
                     addition to the 25-50% increase in the basal insulin.

                  -  The basal insulin rate may be increased an additional amount and additional
                     bolus insulin doses may be given at the discretion of the investigator in
                     order to get a gradual decline in the glucose concentration.

                  -  Blood samples will be collected for the laboratory and glucose will be checked
                     with the study HGM with venous blood every 15 minutes until the glucose level
                     reaches 100 mg/dL. Thereafter, the study HGM will be used to check the glucose
                     levels with venous blood every 5-10 minutes depending on the rate of fall of
                     the glucose level until the end of the study.

                  -  Blood samples will be collected for laboratory determination of hormone
                     concentrations at baseline (before increasing the insulin infusion) and when
                     the glucose levels are <90, <80, <70, and <60 mg/dL.

                  -  Subjects (or parent if appropriate) will be asked questions regarding symptoms
                     of hypoglycemia each time the glucose level is checked with the study HGM.

                  -  Once the endpoint is reached (the first time the glucose is <60 mg/dL using
                     the study HGM), the basal rate will be returned to normal, the subjects will
                     be treated with intravenous glucose and breakfast will be provided.

        4. Prior to discharge, the sensors will be removed and downloaded and the subject's insulin
           pump will be downloaded if possible

      About 6 days (+1 day) following the enrollment visit, subjects will have an inpatient CRC
      admission of approximately 18 hours. Subjects will be admitted at approximately 3:00 PM to
      allow sufficient time to calibrate the sensors before dinner is provided.

        -  Areas where a Guardian RT sensor was worn during the first week will be assessed by
           study personnel for any skin irritation.

        -  The Guardian RT, HGM, and pump data from the previous week will be reviewed and changes
           will be made to diabetes management as needed.

        -  Subjects will continue using the Guardian RT sensor last inserted at home. If the sensor
           is not functioning properly, a new sensor will be inserted.

        -  For subjects of sufficient size, an additional Guardian-RT sensor will be inserted and
           calibrated approximately two hours later. An intravenous catheter will be inserted in an
           arm vein for collection of blood samples during the admission. The area where the
           catheter will be inserted may be numbed with Elamax or EMLA cream prior to catheter
           insertion.

      Once the study endpoint is reached (the first time the glucose is <60 mg/dL using the study
      HGM), the basal rate will be returned to normal and the subjects will be treated with
      intravenous glucose. An additional blood sample will be collected for laboratory
      determination of glucose and hormone concentrations 15 minutes following the treatment with
      intravenous glucose. Subjects will then be given breakfast and discharged. Prior to
      discharge, the sensor(s) will be removed and downloaded. The subject's insulin pump will be
      downloaded if possible.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Approximately 30-50 subjects will be enrolled in this study at five clinical centers with
        approximately 6-10 enrolled at each center.
      
Biospecimen description: 
      Serum