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To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator™ Continuous Glucose Monitoring System (“Navigator”), in children with type 1 diabetes (T1D).
Following use of a masked Navigator for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks.
Subjects averaged 149 hours/week of Navigator use during the first 4 weeks, which decreased slightly to 134 hours/week during weeks 9 to 13 (P=0.006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P=0.02) and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P=0.01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive.
This study indicates that incorporating real-time continuous glucose monitoring into the daily management of T1D in children is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.
Real-time continuous glucose sensors have the potential to revolutionize treatment of type 1 diabetes (T1D). These devices provide patients with information regarding post-prandial and overnight glucose profiles that are rarely, if ever, obtained with conventional self monitoring of blood glucose using home glucose meters. The newest sensors also indicate the direction and rate of change of glucose concentrations and are equipped with alarms for impending or actual hypoglycemia and hyperglycemia. Using computer software programs, patients are able to retrospectively review several days or weeks of glucose values to look for trends and patterns requiring adjustments to their diabetes management. For real-time continuous glucose monitoring to be effective, however, the devices have to have acceptable accuracy and be relatively easy to use.
We previously conducted a randomized trial using the first real time continuous glucose sensor approved by the Food and Drug Administration, the GlucoWatch G2 Biographer™ (“GlucoWatch”, Cygnus, Inc., Redwood City, CA), in children and adolescents with T1D. Use of this device had no effect on HbA1c levels or frequency of hypoglycemia because it was difficult to use, caused skin irritation, was less accurate than expected, and was not worn with sufficient frequency to have an impact on diabetes management.(1) We have now evaluated one of the new real-time continuous glucose monitors the FreeStyle Navigator™ Continuous Glucose Monitoring System (“Navigator”, Abbott Diabetes Care, Alameda, CA). The Navigator uses a glucose oxidase based electrochemical sensor that is inserted subcutaneously and measures interstitial glucose in a range of 20-500 mg/dL every 60 seconds (or 1440 readings a day). The device has adjustable alarms for hypoglycemia and hyperglycemia and for projected high and low glucose values as well as a trend arrow indicating the glucose rate of change (>-2 mg/dL/min, -2 to -1 mg/dL/min, -1 to 1 mg/dL/min, 1 to 2 mg/dL/min, and >2 mg/dL/min). Subjects can enter events, such as when they took insulin, ate, or exercised. The current version of the Navigator requires a 10-hour warm up period. Calibration values are entered approximately 10, 12, 24, and 72 hours after sensor insertion.
The purposes of this pilot study were to examine the feasibility and short-term efficacy of daily use of this continuous glucose monitor in children with T1D receiving insulin pump therapy, to determine how well the Navigator was accepted by young patients and their parents and to explore if there were any limitations on its use based on the age of the patient or other clinical factors.
The study was conducted by the Diabetes Research in Children Network (DirecNet) at five clinical centers. A Data and Safety Monitoring Board and the Institutional Review Boards at each center approved the study protocol, consent form and assent form. A parent or guardian and each subject 7 years and older gave written consent and assent, respectively.
Primary eligibility requirements were: 1) age between 3 and <18 years, 2) diagnosis of T1D, based on clinician impression, of ≥1 year duration, 3) stable insulin regimen using a pump for at least six months prior, 4) home computer with e-mail access and 5) primary caregiver (and subject if ≥9 years of age) comprehend written English. There was not a pre-specified HbA1c requirement for eligibility. Subjects were excluded for: 1) asthma that was medically treated in the prior six months, 2) cystic fibrosis, 3) inpatient psychiatric treatment in the past 6 months (patient or primary caregiver), 4) current use of glucocorticoids, or 5) a medical condition or use of a medication that in the judgment of the investigator could affect wearing of the sensors or the completion of any aspect of the protocol.
The study consisted of three phases: an initial run-in period of approximately one week during which Navigator use was blinded to collect baseline glucose data, a 24-hour inpatient stay in a clinical research center to assess the accuracy of the Navigator (published separately)(2) and to instruct parents and subjects on use of the Navigator, and home use of the Navigator for 3 months. Subjects were provided with the Navigator devices and sensors as well as test strips for the FreeStyle meter.
Thirty-three subjects were enrolled into the run-in phase. Three of the 33 withdrew during this phase because of difficulty keeping the sensor in place, pain with use, or other family priorities. The remaining 30 subjects and/or their primary caregiver were asked to attempt to use the Navigator continuously and were given written instructions on how to use the Navigator data to make real-time management decisions. Each sensor was to be used for up to 5 days (120 hours) as long as it continued to function.
Subjects were asked to download the Navigator and its internal FreeStyle meter to their home computer at weekly intervals. These data were then transmitted to the clinical center and the study coordinating center. Office visits were completed at 3, 7 and 13 weeks and phone calls to the subject or caregiver were made between visits after 0.5, 2, 4, 8 and 10 weeks to review the downloaded glucose data, recommend any changes in diabetes management, and discuss any problems with Navigator use. During each encounter, subjects were asked about the number of symptomatic hypoglycemic episodes they had experienced in the prior 7 days. Episodes were classified as severe if loss of consciousness or seizures occurred.
At each visit, skin areas where a sensor had been worn were evaluated using a modified Draize scale.(3) On 4-point scales, both erythema and edema were assessed for the adhesive area and erythema and induration were assessed for the area of sensor insertion (maximum score 8). A total score of 6 or greater was classified as an adverse event, a score of 3-5 was classified as moderate and 1 or 2 as mild skin changes.
At baseline and at each follow-up visit, hemoglobin A1c (A1c) was measured with the DCA 2000® + Analyzer (Bayer, Inc., Tarrytown, NY). Previously, we demonstrated that this method has a high degree of concordance with HbA1c measurements made using the Tosoh A1c 2.2 Plus Glycohemoglobin Analyzer method using cation-exchange HPLC methodology at the DCCT/EDIC laboratory at the University of Minnesota laboratory.(4)
At baseline and 13 weeks, the primary caregiver and subject (if ≥9 years of age) completed the PedsQL Diabetes Module(5) (a measure of children’s diabetes-related quality of life) and were interviewed by telephone using the Diabetes Self Management Profile(6) (measure of treatment adherence). Additionally, the Continuous Glucose Monitor Satisfaction Scale(7) was completed at 13 weeks. Based on suggestions made by research coordinators after a previous similar study, 7 items were added (Items #38-44). The item-total correlations for these new items were all statistically significant (Pearson correlation coefficients =0.49 to 0.89 for parent response and 0.35 to 0.80 for subject response) and the internal consistency of the revised scale was satisfactory (alpha = 0.97 and 0.96 for parent and subject responses, respectively).
At the 13-week visit, subjects were given the option to continue wearing the Navigator for another 13 weeks and return for an additional clinic visit at 26 weeks. Continuing subjects were supplied with sensors and FreeStyle meter test strips. This report is limited to data from the first 13 weeks.
Glycemic indices based on the Navigator data were calculated giving equal weight to each of the 24 hours of the day. Hypoglycemia area (a composite measure of percentage and severity of Navigator values ≤70 mg/dL) was defined as the area below 70 mg/dL. Similarly, the hyperglycemia area was defined as the area above 180 mg/dL. Glucose lability (variation) was quantified according to the standard deviation (SD), the mean amplitude of glycemic excursions (MAGE)(8) and the mean absolute rate of change.(9)
Statistical analyses of changes in A1c levels, questionnaire responses and glycemic indices were performed using paired t-tests comparing (1) baseline with weeks 9-13 values and (2) weeks 1-4 with weeks 9-13. The paired differences were verified to have an approximate normal distribution.
The average age of the 30 subjects was 11.2 ± 4.1 years (range 4 to 17) and 40% were female. Mean duration of diabetes was 5.8 ± 3.0 years. Mean A1c was 7.1 ± 0.6%, with 15 of the subjects having an A1c ≤7.0% (mean age 11.1 years) and 15 having an A1c >7.0% (mean age 11.3 years). None of the subjects reported a severe episode of hypoglycemia in the 6 months prior to the study.
The 1, 3 and 7-week visits were completed by all 30 subjects. Two (7%) subjects (age 4 with baseline A1c of 6.8% and age 11 years with baseline A1c of 6.9%) dropped out of the study following the 7-week visit, one due to difficulty wearing the sensor and the other due to perceived insufficient accuracy. The remaining 28 subjects completed the 13-week visit. There were 19 unscheduled visits from 11 subjects due to problems/questions with the Navigator (N=12), skin reaction (N=3), to pick up study supplies (N=2), to review insulin dose guidelines for persistent hyperglycemia (N=1) or to download their insulin pump (N=1). Ninety-nine percent of the scheduled phone calls were completed.
During the first 4 weeks of unblinded sensor use, the sensor was worn an average of 149 ± 22 hours per week (out of a maximum of 168 hours in a week), with an average 120 ± 27 hours of glucose readings (out of a maximum of 148 hours per week accounting for the 10-hour warm-up period for each sensor). Navigator use decreased slightly throughout the study averaging 134 ± 37 hours of wear and 104 ± 39 hours of glucose values per week during weeks 9 to 13 (P=0.006 and 0.003, respectively). Seventeen (57%) of the 30 subjects averaged at least 6 days of Navigator use per week and only 2 subjects used the device for less than 4 days per week. Among 9 subjects who reported using the Navigator less than 7 days per week at the 13-week visit, reasons reported for lack of use included: too busy (N=4), skin irritation (N=1), trouble with calibration (N=1), lost receiver (N=1), ran out of sensors (N=1) and difficulty with adhesion and bleeding at insertion site (N=1).
The mean number of FreeStyle glucose meter measurements (excluding measurements made for calibration) declined steadily from 5.0 ± 2.0 per day during the first 4 weeks to 4.1 ± 2.5 per day during weeks 5 to 8 to 3.8 ± 2.2 per day during weeks 9 to 13 (p<0.001). During weeks 9 to 13, 29% of subjects averaged <2.0 meter measurements a day, 18% averaged 2.0 to <4.0 measurements a day, 39% averaged 4.0 to <6.0 measurements a day, and 14% averaged 6.0 or more measurements a day.
During the 13 weeks of the study, 626 sensors were used by the 30 subjects. Seventy-six (12%) of the 626 sensors never provided glucose data, either because of insertion problems, inability to calibrate, or other reason. Among the other 550 sensors, the median time from insertion to the last glucose value was 98 hours (interquartile range 58 to 120), with 52 (9%) functioning for <24 hours, 69 (13%) for 24 to <48h, 70 (13%) for 48 to <72 hours, 71 (13%) for 72 to <96 hours, and 288 (52%) for 96 to 120 hours. Thirty-two Navigator kits from 18 subjects were replaced during the study, 19 due to a broken receiver or transmitter and 13 due to the receiver and or transmitter not working properly.
Twenty-six of the 28 subjects completing the 13-week visit elected to continue use of the Navigator during the optional continuation phase. The reasons given for the two who declined were (1) problems with calibrations and (2) embarrassment caused by the frequent alarms in class and difficulties with the timing of the required calibrations.
For the 28 subjects completing the 13-week visit, A1c values dropped from 7.1 ± 0.6% at baseline to 6.8 ± 0.7% at 13 weeks (p=0.02, Table I). The change in A1c was 0.0 ± 0.4% for the 13 subjects whose baseline A1c was ≤7.0% (mean 6.6 ± 0.4%) whereas A1c levels decreased from 7.6 ± 0.4% to 7.0 ± 0.7% in the 15 subjects whose baseline A1c was >7.0%. Among the 15 subjects with baseline A1c >7.0%, a decrease of 0.5% or more from baseline to 13 weeks occurred in 9 (60%). Mean glucose concentration dropped and the percentage of sensor values in the target range of 71 to 180 mg/dL rose during the first 4 weeks and remained steady through weeks 9 to 13 (p=0.002 and p=0.01 respectively for change from baseline to 9-13 weeks). Glycemic variation also decreased during the study period (Table I).
The percentage of Navigator values ≤70 mg/dL was 4.5% at baseline, 5.1% during weeks 1 to 4 and 5.5% during weeks 9 to 13 (p=0.07 comparing baseline to 9-13 weeks), with a similar but less pronounced trend in the percentage of values ≤60 mg/dL (Table I). The percentage of values ≤70 mg/dL was 2.5% at baseline and 5.0% at 13 weeks for subjects whose baseline A1c was >7.0% (p=0.06), and 6.6% and 6.1% respectively for subjects with baseline A1c ≤7.0% (P=0.87). There were no events meeting criteria for severe hypoglycemia (seizure or loss of consciousness) during the 13 weeks of the study, including no cases in which glucagon or a similar intervention was needed due to lack of responsiveness.
Subjects and parents reported high overall satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale at 13 weeks with average item scores of 3.6 for subjects and 3.9 for parents on a 5-point Likert scale. Mean item scores were more favorable than “Neutral” (above 3.0) on 42 of the 44 items (95%) for parents and on 40 (91%) of items for children. It is particularly noteworthy that over 70% of both patients and parents agreed that use of the Navigator made adjusting insulin easier (item #2), made them more sure about making diabetes decisions (#3), showed patterns in blood glucose not seen before (#20), clarified how everyday habits affected blood sugar levels (#23) and did not cause more family conflicts (#25) (Table II; available at www.jpeds.com).
Scores on the Diabetes Self Management Profile (higher score denotes better adherence, possible range 0-86) were similar at baseline and 13 weeks (subjects: 64 ± 11 vs. 63 ± 10, p=0.39; parents: 63 ± 10 vs. 64 ± 10, p=0.69). There were also no meaningful changes in PedsQL scores (lower score denotes higher quality of life, possible range 0-112) over the course of the study (subjects: 26 ± 10 vs. 26 ± 12, p=0.81; parents: 31 ± 9 vs. 31 ± 9, p=0.91).
Most subjects tolerated the Navigator placement well. Two subjects had severe skin reactions related to the adhesive of the sensor mount. When the skin reaction resolved, both subjects resumed Navigator use with an under-bandage placed between the sensor mount and the skin.
At the 13-week visit, 8 (29%) of the 28 subjects had acute skin changes reflective of Navigator use (moderate in 14% and mild in 14%), and 11 (39%) were considered to have non-acute changes such as scabbing 32%, dry skin 21% and changes in pigmentation 7%.
The primary purpose of this pilot study was to assess whether real-time continuous glucose monitoring could become an integral part of daily diabetes management for children with T1D on insulin pump therapy. The overall results in this regard using the Navigator were positive. Specifically, the majority of subjects used the Navigator on an almost daily basis, parents and patients were very satisfied with the data provided by the device, there was a significant decrease in the proportion of glucose values above the target range, and glucose variability was reduced. Improvements in glycemic control were seen immediately after initiation of continuous glucose monitoring and were sustained for the duration of the 13-week study.
It has been postulated that glucose variability, considered in combination with A1c, may be a significant indicator of the risk for long-term complications.(10, 11) A previous DirecNet study demonstrated that continuous glucose monitoring profiles provide an effective means to assess changes in glucose variability in diabetes intervention studies.(12) It is therefore noteworthy that the mean amplitude of glycemic excursions (MAGE) was reduced during this study.
Subject and parent satisfaction with the Navigator was high, and almost all subjects when given the option elected to continue use of the Navigator after the first 13 weeks of the study. These findings are in marked contrast to the results of our study of the GlucoWatch,(1) in which sensor use averaged less than 15 hours per week after 3 months (compared with 134 hours per week with the Navigator), and subjects and parents generally were dissatisfied with the GlucoWatch (mean scores on the 5-point Continuous Glucose Monitoring Satisfaction Scale were 2.7 for subjects and 2.7 for parents compared with 3.6 and 3.9 respectively for the Navigator).(7) One potential concern with real-time continuous glucose monitoring is that patients and parents might not be able to deal with all the additional data provided by the devices. Just the opposite was observed in this study, as subjects and their parents felt that the Navigator made it easier to make insulin dose adjustments and diabetes management decisions and reduced family conflict.
Navigator use was not without problems. Two subjects had severe skin reactions due to the adhesive tape. However, both subjects considered the benefits of Navigator use to be greater than the harm caused by the skin reaction and elected to resume use of the Navigator once the skin reaction had resolved. Skin reactions were much less of a problem with the Navigator than what we found with use of the GlucoWatch.(1) With some of the younger children, the size of the sensor and transmitter platform made placement of the sensor difficult. Damage to the receivers was also a problem and future versions of the Navigator would benefit from increased ruggedness as well a smaller size for long term use in children and adolescents.
Although none of the subjects had a severe hypoglycemic event during the study, it was disappointing that use of the Navigator did not decrease the percentage of sensor glucose levels < 70 mg/dl in the patients who were very well controlled with A1c levels ≤7.0% on entry in the study. Moreover, in the other half of patients, lowering A1c values from 7.6% to 7.0% was associated with a modest increase in the percentage of sensor values that were ≤70 mg/dL. It should be noted, however, that this pilot project did not specifically target prevention of hypoglycemia in very well controlled patients as a primary aim of the study.
The results of this pilot and feasibility study are encouraging in indicating that incorporating real-time continuous glucose monitoring into the daily management of T1D in children is feasible and viewed as helpful by both patients and parents. However, the results must be viewed cautiously because the study did not include a concurrent control group, subject contact with the clinical site was more frequent than the amount that would occur in usual practice, and follow up was only for 3 months. In addition, the results can not be generalized to all children with T1D because the study included a select group of subjects who were all insulin pump users, most of whom had an excellent A1c level at baseline and all of whom had a home computer. Randomized clinical trials are needed to more fully evaluate the added value that real-time continuous glucose monitoring provides to patients in comparison with standard SMBG alone. It will also be important to determine whether these systems can reduce the risk of asymptomatic and symptomatic hypoglycemic events in patients with low A1c levels without sacrificing overall diabetes control. The results of this study provide compelling evidence that support the feasibility of such large-scale long-term trials in children with T1D.
Lead authors: Bruce Buckingham, MD; Roy W. Beck, MD, PhD; William V. Tamborlane, MD; Dongyuan Xing, MPH; Craig Kollman, PhD. Additional writing committee members (alphabetical): Rosanna Fiallo-Scharer, MD; Nelly Mauras, MD; Katrina J. Ruedy, MSPH; Michael Tansey, MD; Stuart A. Weinzimer, MD; Tim Wysocki, PhD, ABPP
The DirecNet Study Group
Clinical Centers: (Listed in alphabetical order with clinical center name, city, and state. Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO: Peter Chase, Rosanna Fiallo-Scharer, Laurel Messer, Barbara Tallant; Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA: Eva Tsalikian, Michael Tansey, Linda Larson, Julie Coffey, Joanne Cabbage; Nemours Children’s Clinic, Jacksonville, FL: Tim Wysocki, Nelly Mauras, Larry Fox, Keisha Bird, Kim Englert; Division of Pediatric Endocrinology and Diabetes, Stanford University, Stanford, CA: Bruce Buckingham, Darrell M. Wilson, Jennifer Block, Paula Clinton, Kimberly Caswell; Department of Pediatrics, Yale University School of Medicine, New Haven, CT: Stuart Weinzimer, William Tamborlane, Elizabeth Doyle, Heather Mokotoff, Amy Steffen; Coordinating Center: Jaeb Center for Health Research, Tampa, FL: Roy Beck, Katrina Ruedy, Craig Kollman, Dongyuan Xing, Mariya Dontchev, Cynthia Stockdale; University of Minnesota Central Laboratory: Michael Steffes, Jean M. Bucksa, Maren L. Nowicki, Carol Van Hale, Vicky Makky; National Institutes of Health: Gilman Grave, Mary Horlick, Karen Teff, Karen K. Winer; Data and Safety Monitoring Board: Dorothy Becker, Patricia Cleary, Christopher M. Ryan, Neil White, Perrin White
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