Background: DirecNet

1
Background DirecNet

• Diabetes Research in Children Network
• NIH funded collaborative study group
• 5 clinical centers, central laboratory,
  coordinating center, and representatives form
  NICHD and NIDDK
• Objective to critically evaluate the clinical
  usefulness of current and future glucose sensors
  in youth with TIDM

2
Background CGMS Accuracy Study

• CGMS was first FDA approved sensor
• Has been used to characterize glucose profiles in
  children by many investigators
• Most CGMS validation studies were performed with
  adults and used comparisons to meter instead of
  reference laboratory serum glucose levels
• Recent reports have questioned accuracy and
  reproducibility of CGMS readings

3
Objective

• To assess the accuracy of the CGMS inc children
  and adolescents with type 1 diabetes when
  compared with reference serum glucose levels
• Examined accuracy under three conditions
• Spontaneous fluctuations in 24 hour period
• Acute hyperglycemia (1.75gm/kg CHO liquid
  meal)
• Acute hypoglycemia (0.05-0.10 u Regular
  insulin intravenous bolus)

4
Methods Overall

• Subjects were admitted to the CRC for 24-26 hrs
• IV catheter was inserted to obtain serum glucose
  levels to be measured by central lab
• Blood samples were obtained every 60 min during
  the day, and every 30 min during the night
  (930p-630a)
• Blood samples were also obtained with symptomatic
  hypoglycemia (if FS lt 65 mg/dL)
• Skin assessment at time of discharge and in 3-5
  days following discharge

5
Methods CGMS

• CGMS were inserted by study staff either on day
  of admission or 1-2 days prior to admission to
  assess full 72 hour life of sensor
• Four fingerstick blood sugars done with a One
  Touch Ultra meter were entered into the CGMS for
  calibration
• Sensors were replaced if they failed
• Simultaneous use of a second CGMS was offered as
  an option.
• Sensors were inserted into abdomen or buttucks

6
Statistical Methods CGMS Measurements

• CGMS glucose measurements were matched to
  reference measurements from blood samples drawn
  within 2.5 min of each other
• CGMS time was adjusted by 2.5 min to account for
  averaging of glucose levels made over the
  previous 5 min
• When comparing CGMS monitors simultaneously,
  sensor values were matched within 2.5 min of each
  other

7
Statistical Methods Modified Sensors

• During the course of the study, Medtronic MiniMed
  changed the manufacturing process of the sensor
  that had been in place since 1999
• Sensor fabrication process was modified
• Accuracy analyses were conducted separately with
  the original and modified sensors

8
Subjects ( N 91)

• Mean age 9.9 4.1 yrs
• Gender 45 M, 46 F
• Race 85 White
• Duration T1DM 4.7 3.2 yr
• Mean HbA1c 7.8 1.2

Pump (43)
Injections (57)
Diabetes Therapy
9
Sensor Function
Day of sensor insertion
Percent ()
(N/A)
6 of all possible readings were skipped
10
CGMS Accuracy Summary Statistics (N 6,778
sensor reference pairs)
11
Original vs Modified Sensors Comparison of
Accuracy
Original Sensors
Modified Sensors
P-Value
N5,658 Paired Values
N1,120 Paired Values
12
Original vs Modified Sensors Comparison of
Accuracy
Original Sensors N5,658 Paired Values
ISO Criteria Met According to Reference Glucose
Level
Modified Sensors N1,120 Paired Values
ISO for Ultra Meter 94

Percent ()
Plt.05 Plt.001
ISO criteria for reference BG 75 mg/dL, SG
within 15 mg/dL for reference BG gt75 mg/dL, SG
value within 20
13
Original vs Modified Sensors Comparison of
Accuracy Variation Among Sensors
Original Sensors
Modified Sensors
P-Value
N25 Sensors
N112 Sensors

• Sensors with Median RADlt10
• Sensors with Median RADlt20
• Sensors with Median RADlt30
• Sensors with ?80 of Values Meeting ISO Criteria
• Sensors with ?60 of Values Meeting ISO Criteria

9 54 80 9 35
36 88 100 24 80
0.01 lt0.001 lt0.001 0.07 lt0.001
Sensors were included if they had at least 10
paired readings
14
Original vs Modified SensorsPrecision of 2
Simultaneous CGMS
15
Conclusions

• Sensors were tolerated well by children aged
  3-17, and there were no adverse events
• Most sensors functioned for full three days
• Overall percentage of skipped readings was low

16
ConclusionsOriginal Sensors

• Original sensors were frequently inaccurate in
  detecting glucose excursions and detecting
  hypoglycemia
• Accuracy was better during hyperglycemia than
  during hypoglycemia
• Precision (comparing two CGMS worn
  simultaneously) was poor (r .77)

17
ConclusionsModified Sensors

• Modified sensors were more accurate on all
  measures
• Modified sensors had better precision (r
  .92)
• Further research is necessary to determine if
  detection of hypoglycemia will be better with the
  modified sensors

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• Barbara Davis Center
• H. Peter Chase
• Rosanna Fiallo-Scharer
• Jennifer Fisher
• University of Iowa
• Eva Tsalikian
• Michael Tansey
• Linda Larson
• Nemours Childrens Clinic
• Tim Wysocki
• Nelly Mauras
• Kristen Gagnon
• University of Minnesota Central Lab
• Michael Steffes
• Jean Bucksa
• Maren Nowicki

• Stanford University
• Bruce Buckingham
• Darrell Wilson
• Jennifer Block
• Yale University
• William Tamborlane
• Stuart Weinzimer
• Elizabeth Boland
• Jaeb Center for Health Research
• Roy Beck
• Katrina Ruedy
• Craig Kollman
• Andrea Booth
• Gladys Bernett