Evaluation of Novel Trend Arrow Adjustment Tool for Diabetes Patients Using Continuous Glucose Monitoring to Guide Insulin Bolus Adjustment (TAAT Study)
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      Continuous glucose monitoring (CGM) provides up to 288 blood glucose levels per day, updated
      every 5 minutes and displayed in real-time on the insulin pump, which can be used to enhance
      delivery of insulin through pump therapy. In addition this real-time CGM data includes "trend
      arrows" which indicate when the blood glucose is rapidly falling or rising thus enabling the
      pump user to make immediate adjustments in insulin delivery to prevent subsequent low or high
      blood sugars. The trend arrows are displayed when the blood glucose is rapidly falling or
      rising. For example, if the glucose is increasing by 1-2 mmol/L over 20 minutes, a single
      upward arrow alerts the pump wearer, who can then decide to give a bolus of insulin or
      increase the meal bolus. Should the glucose level be increasing at a rate greater than
      2mmol/L over 20 minutes, 2 upward arrows are displayed and the user could decide to give a
      larger bolus. The purpose of the bolus adjustment is to add insulin for the predicted rise in
      glucose to prevent or reduce subsequent hyperglycemia. Similarly, a decrease in the insulin
      bolus is advised if glucose levels are falling as evidenced by one or two downward arrows.

      However, effective strategies for adjusting insulin boluses based on CGM trend arrows are
      lacking. The JDRF CGM Study Group recommended that boluses be adjusted based on trend arrows
      using a standard 10-20% increase/decrease of the total original recommended bolus dose (10%
      for one arrow up or down, and 20% for two arrows up or down), with the original bolus dose
      calculated by the pump calculator (i.e. Bolus Wizard). However, the original recommended
      bolus dose is dependent on the amount of food to be consumed (grams of carbohydrate) and the
      current blood glucose (if above or below target range), as well as the amount of active
      insulin, and therefore increasing or decreasing the total recommended bolus by 10-20% may
      overcompensate for the trend arrows and result in postprandial hypoglycemia. Attempts to use
      the10/20% formula within CHEO's large pediatric pump/CGM population resulted in low
      acceptance and adherence by CGM users.

      The CGM TIME Trial Study Group develop an innovative tool for adjusting boluses for CGM trend
      arrows based on the patient's own insulin sensitivity factor (ISF). The Trend Arrow
      Adjustment Tool formula is: if CGM shows a single arrow up or down: adjust bolus by +/-
      (1.5/ISF) and for 2 arrows up or down +/- (3/ISF). Use of the Trend Arrow Adjustment Tool
      within the CGM TIME Trial appears to lead to more appropriate adjustment in bolus dosing, and
      more effective prevention of subsequent hyper- and hypoglycemia. Furthermore, this tool
      appears to have excellent uptake amongst the TIME Trial participants, with observations that
      there is continued usage of the tool throughout the 12 month study, and greater satisfaction
      with this component of CGM. However, the tool has not been systematically evaluated.

      The proposed study will evaluate the Trend Arrow Adjustment Tool, to determine its
      effectiveness in reducing postprandial hyper- and hypoglycemia, as well as parent,
      child/youth satisfaction, and ease of use of the tool based on self-report measures.
      Comparison will be made with the 10/20% bolus adjustment & also to no adjustments to meal
      boluses (i.e. ignoring CGM trend arrows). Should use of the Trend Arrow Adjustment Tool lead
      to more time spent within the target glucose range, this will have immediate clinical benefit
      for patients, including improved quality of life, and potentially a reduction in HbA1c and
      prevention of long-term complications.
    

Detailed description: 
      Detailed protocol:

      Phase 1(inpatient evaluation):

      This part of the study will take place in a standardized outpatient setting (CHEO Medical Day
      Unit/Clinic). The CGM trend arrows will be stimulated using two typical clinical scenarios:
      oral fast acting carbohydrate (to stimulate upward trend arrows) and exercise (to stimulate
      downward trend arrows).

      40 participants will be enrolled in this phase of the study (20 of whom will have oral fast
      acting carbohydrate and 20 of whom will engage in exercise). Once trend arrows have been
      triggered, the subjects will receive a standardized meal, and an adjusted insulin bolus.
      Comparison will be made between the Trend Arrow Adjustment Tool (based on the patient's own
      insulin sensitivity factor) and the standard bolus adjustment recommendations (i.e. +/-
      10/20%, based on the STAR 1 Trial and JDRF CGM Study Group). Phase 1 of the study will lead
      directly to Phase 2's outpatient evaluation.

      Upward CGM trend arrows (Group 1):

        1. Participants will arrive fasting at the outpatient clinic. They will have been asked to
           change their pump and CGM the morning of the previous day and to ensure that both are
           functioning well prior to arrival. An iPro2 (blinded) continuous glucose monitor will be
           inserted subcutaneously, to provide a second recording of glucose trends. Each subject
           will be randomized, in a 1:1 ratio, to either the Trend Arrow Adjustment Tool (based on
           the patient's own insulin sensitivity factor) or the standard bolus adjustment
           recommendations (i.e. +/- 10/20%, based on the STAR 1 Trial and JDRF CGM Study Group).

        2. Baseline blood glucose will be checked using a validated blood glucose meter, via
           capillary sampling.

        3. At study onset, target blood glucose is 3.6-11mmol/L. If CGM shows trend arrows, the
           participant will proceed directly to a meal. If there are no upward trend arrows, a
           preliminary dose of Glucodex (oral fast acting carbohydrate) will be given. The
           participant will wait for up to one hour or until CGM ↑↑ are triggered, and will then
           proceed to a meal.

        4. The participant will be given a standardized meal (containing a fixed amount of
           carbohydrate, fat and protein, appropriate for subject's weight) and a bolus of insulin
           will be given, via the insulin pump, using either the Trend Arrow Adjustment Tool or the
           standard 10/20% formula, to adjust the bolus dosage recommended by the bolus wizard.

        5. Glucose levels will be monitored using hourly capillary blood samples, CGM and iPro2.
           Glucose levels </= 3.5mmol/L or if < 4.0 mmol/L and the subject complains of
           hypoglycemic symptoms, will be treated as per standard hypoglycemia management plan.

        6. Glucose monitoring will continue for 3 hours postprandially, to obtain an adequate
           glycemic profile for examination.

        7. A second dose of Glucodex will then be given, to trigger trend arrows again. Subjects
           will wait for one hour or until CGM ↑↑ are triggered, and will then proceed to a second
           standardized meal.

        8. A bolus of insulin will be given, via the insulin pump, using either the Trend Arrow
           Adjustment Tool or the standard 10/20% formula, to adjust the bolus dosage recommended
           by the bolus wizard. The same bolus adjustment method will be used for both meals in the
           same participant.

        9. Glucose monitoring will continue for a further 3 hours postprandially, to obtain an
           adequate glycemic profile for examination.

       10. Prior to discharge, the participant and their parents/guardians, will be trained in the
           use of the Trend Arrow Adjustment Tool or the 10/20% bolus adjustment formula, (matching
           the bolus adjustment protocol used in the acute part of the study), and asked to
           continue to use this for the next 7 days. Participants will be requested to continue to
           use the iPro2 sensor for 6 days and to upload CGM data daily via Carelink Personal. A
           log book will be given, to record each time a trend arrow is observed and the methods
           used to adjust the bolus.

      Downward trend arrows (Group 2):

        1. Subjects will arrive fasting at the outpatient clinic. An iPro2 continuous glucose
           monitor will be inserted subcutaneously, to provide a second recording of glucose
           trends. Each subject will be randomized, in a 1:1 ratio, to either the Trend Arrow
           Adjustment Tool (based on the patient's own insulin sensitivity factor) or the standard
           bolus adjustment recommendations (i.e. +/- 10/20%, based on the STAR 1 Trial and JDRF
           CGM Study Group).

        2. Baseline blood glucose will be checked, via capillary sampling.

        3. At study onset, blood glucose should be in a 6-11mmol/L target range.

        4. If CGM shows trend arrows, subjects will proceed directly to a meal.

        5. If there are no downward trend arrows, the participant will carry out exercise, using a
           treadmill. Exercise will be for a period of 15 minutes, followed by a 5 minute rest
           period; and repeated as tolerated until downward trend arrows are triggered. CGM will be
           monitored for trend arrows. Exercise will be halted if CGM shows ↓↓ or child complains
           of hypoglycemic symptoms. At this point, capillary blood glucose will be checked.
           Glucose levels </= 3.5mmol/L, or < 4mmol/L with hypoglycemia symptoms, will be treated
           according to the standard hypoglycemia management plan.

        6. The participant will then be given a standardized meal (containing a fixed amount of
           carbohydrate, fat and protein, appropriate for the subject's weight) and a bolus of
           insulin will be given, via the insulin pump, using either the Trend Arrow Adjustment
           Tool or the standard 10/20% formula, to adjust the bolus dosage recommended by the bolus
           wizard.

        7. Glucose levels will be monitored using hourly capillary blood samples and CGM. Any
           glucose levels </= 3.5mmol/L, or < 4mmol/L with hypoglycemic symptoms, will be treated
           as per standard hypoglycemia management plan. Glucose monitoring will continue for 3
           hours, to obtain an adequate glycemic profile for analysis.

        8. A second standardized meal will then be given.

        9. A bolus of insulin will be given, via the insulin pump, using either the Trend Arrow
           Adjustment Tool or the standard 10/20% formula, to adjust the bolus dosage recommended
           by the bolus wizard. The same bolus adjustment method will be used at both time points
           for the participant.

       10. Glucose monitoring will continue for a further 3 hours postprandially, to obtain an
           adequate glycemic profile for examination.

       11. Prior to discharge, the participant and their parents/guardians, will be trained in the
           use of the Trend Arrow Adjustment Tool or the 10/20% bolus adjustment formula, (matching
           the bolus adjustment protocol used in Phase 1 of the study), and asked to continue to
           use this for the next 7days. Participants will be requested to continue to use the iPro2
           sensor for 6 days and to upload CGM data daily via Carelink Personal. A log book will be
           given, to record each time a trend arrow is observed and the methods used to adjust the
           bolus.

      Protocol Phase 2: Outpatient Evaluation of the Trend Arrow Adjustment Tool

      This will be a single site, randomized, controlled, single blinded crossover study, involving
      the same 40 subjects. Each participant will complete a 3 week assessment. Phase 1 will lead
      directly into Phase 2.

      All subjects and their parents will have received standardized education on insulin pump
      therapy and CGM, with review and optimization of their basal rates, insulin sensitivity
      factor(s), and insulin carbohydrate ratios, during the week prior to participation in the
      study.

      For the first week of the study, subjects will administer adjusted meal insulin boluses (i.e.
      either the Trend Arrow Adjustment Tool, or the 10/20% bolus adjustment formula, whichever
      they were randomized to receive in Phase 1).

      In week 2, subjects will administer standard meal insulin boluses (i.e. using Bolus Wizard
      recommendations only; ignoring any CGM trend arrows).

      In week 3, subjects will crossover to the alternate arm of the study.

      Participants will be provided with CGM sensors for use during the study. Each participant
      will be asked to wear an iPro2 (blinded CGM) during the first 6 days of each week long
      assessment, to increase CGM data capture. A research co-ordinator will visit the participants
      at home to insert the iPro2 sensors, at the start of weeks 2 and 3. At the beginning of week
      3, the participants and their parents/guardians will be trained in the crossover method of
      bolus adjustment.

      Participants will be given a log book and asked to record each time a trend arrow is observed
      (at meal times) and whether they adjusted the subsequent meal bolus, as recommended. If the
      adjustment was not used, they will be asked to explain why they didn't use the recommended
      bolus adjustment tool.

      Participants will be asked to upload to CareLink Personal weekly, throughout the study. Study
      staff will use CareLink Professional to assess glycemic variability and adherence to diabetes
      management.

      At the end of each week long assessment period, subjects will be given a questionnaire to
      examine their use and satisfaction with the assigned meal bolus method.
    

Intervention name(s): Trend Arrow Adjustment Tool; 10/20% bolus adjustment
Intervention type(s): Other; Other
Intervention description(s): The Trend Arrow Adjustment Tool formula is: if CGM shows a single arrow up or down: adjust bolus by +/- (1.5/ISF) and for 2 arrows up or down +/- (3/ISF). Where ISF is the patients own insulin sensitivity factor.; The 10/20% bolus adjustment formula is: if CGM shows a single arrow up or down: adjust bolus by +/- 10% and for 2 arrows up or down +/- 20%.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Insulin Infusion Systems; Blood Glucose