Artificial Pancreas and Remote Monitoring During a T1DM Youth Ski Camp

This proposal aims to demonstrate the superiority of the Closed-Loop Control (CLC), also known as Artificial Pancreas (AP) named Tandem t:slim X2 with Control-IQ Technology and assess usability in a supervised setting in a controlled environment compared with state-of-the-art Sensor-Augmented Pump (SAP) therapy for the treatment of type 1 diabetes (T1D) in adolescents. Phase 1 participants (13-18 years old) and Phase 2 participants (6-12 years old) will be assessed during a \~48 hour ski camp; Upon completion of the ski camp, Phase 2 participants (6-12 years old) will also be assessed during a \~78 hour home use.

• Tandem t:slim X2 with Control-IQ Technology + Dexcom G6 (Device), also known as Artificial Pancreas, Automated Insulin Delivery Device: Subjects will use the Tandem t:slim X2 with Control-IQ Technology and Dexcom G6 CGM to control their glycemia. The Tandem t:slim X2 with Control-IQ device is an automated insulin delivery pump that automatically adjusts insulin delivery to predicted and prevailing glucose levels, as measured by a Dexcom G6 continuous glucose monitor \[CGM\].
• Dexcom CGM G5 (Device), also known as Continuous Glucose monitoring: The Dexcom G5 CGM is a subcutaneous glucose sensor that provides an estimate of the prevailing blood glucose concentration approximately every 5 minutes.The Dexcom G5 sensor alerts the user if the prevailing glucose concentration is higher or lower than predetermined thresholds, or if it is changing too fast. In addition, the Share/Follow functionality of the Dexcom G5 allows up to 5 people ("followers") to receive in real-time information about the current blood glucose concentration and rate of change. The Dexcom G5 system will be used by participants and clinical study staff to monitor glucose levels 24h/day during the camp, ensure participants safety, and compute glycemic control outcomes
• Continuous Subcutaneous Insulin Infusion (Device), also known as Insulin pump: Subjects will use a subcutaneous pump to deliver insulin and control their glycemia.

Primary outcomes

• Percent Time Spent Between 70 and 180 mg/dL [Overall [48hr study admission]]: The primary outcome was the percent time spent between 70 and 180 mg/dL during the 48hr study admission.
• Percent Time Spent Between 70 and 180 mg/dL [Daytime [7am - 11pm]]: This outcome looks at the percentage of time spent between 70 and 180 mg/dL during the Daytime, defined as 7am-11pm.
• Percent Time Spent Between 70 and 180 mg/dL [Overnight [11pm - 7am]]: This outcome looks at the percentage of time spent between 70 and 180 mg/dL during the Overnight, defined as 11pm-7am.
• Percent Time Spent Between 70 and 180 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: This outcome looks at the percentage of time spent between 70 and 180 mg/dL during the Skiing periods, defined as 9:30am-noon and 1:30pm-4pm.

Secondary outcomes

• Percent Time Spent <50 mg/dL [Overall [48hr study admission]]: The percentage of time spent below 50 mg/dL during the Overall period. CGM measured blood sugar values below 50 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 50 mg/dL is considered a better outcome.
• Percent Time Spent <54 mg/dL [Overall [48hr study admission]]: The percentage of time spent below 54 mg/dL during the Overall period. CGM measured blood sugar values below 54 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 54 mg/dL is considered a better outcome.
• Percent Time Spent <60 mg/dL [Overall [48hr study admission]]: The percentage of time spent below 60 mg/dL during the Overall period. CGM measured blood sugar values below 60 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 60 mg/dL is considered a better outcome.
• Percent Time Spent <70 mg/dL [Overall [48hr study admission]]: The percentage of time spent below 70 mg/dL during the Overall period. CGM measured blood sugar values below 70 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 70 mg/dL is considered a better outcome.
• Percent Time Spent >180 mg/dL [Overall [48hr study admission]]: The percentage of time spent above 180 mg/dL during the overall period. CGM measured blood sugar values above 180 mg/dL are considered to be undesirable. Thus, less time spent above 180 mg/dL is considered a positive outcome.
• Percent Time Spent >250 mg/dL [Overall [48hr study admission]]: The percentage of time spent above 250 mg/dL during the Overall period. CGM measured blood sugar values above 250 mg/dL are considered to be undesirable. Thus, less time spent above 250 mg/dL is considered a positive outcome.
• Percent Time Spent >300 mg/dL [Overall [48hr study admission]]: The percentage of time spent above 300 mg/dL. CGM measured blood sugar values above 300 mg/dL are considered to be undesirable. Thus, less time spent above 300 mg/dL is considered a positive outcome.
• Mean Glucose [Overall [48hr study admission]]: Mean glucose is a measure of the average CGM value in mg/dL during the Overall period. A lower value, without approaching hypoglycemia, is indicative of a desirable outcome.
• Glucose Variability [Overall [48hr study admission]]: Variability of glucose during the Overall period
• Insulin [Overall [48hr study admission]]: Amount (U/kg) of insulin administered during the Overall period
• Carbohydrate (CHO) Treatment [Overall [48hr study admission]]: The amount of carbohydrates in grams administered as treatment for hypoglycemia in the Overall period.
• Percent Time Spent <50 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent below 50 mg/dL during the Daytime period. CGM measured blood sugar values below 50 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 50 mg/dL is considered a better outcome.
• Percent Time Spent <54 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent below 54 mg/dL during the Daytime period. CGM measured blood sugar values below 54 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 54 mg/dL is considered a better outcome.
• Percent Time Spent <60 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent below 60 mg/dL during the Daytime period. CGM measured blood sugar values below 60 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 60 mg/dL is considered a better outcome.
• Percent Time Spent <70 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent below 70 mg/dL during the Daytime period. CGM measured blood sugar values below 70 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 70 mg/dL is considered a better outcome.
• Percent Time Spent >180 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent above 180 mg/dL during the Daytime period. CGM measured blood sugar values above 180 mg/dL are considered to be undesirable. Thus, less time spent above 180 mg/dL is considered a positive outcome.
• Percent Time Spent >250 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent above 250 mg/dL during the Daytime period. CGM measured blood sugar values above 250 mg/dL are considered to be undesirable. Thus, less time spent above 250 mg/dL is considered a positive outcome.
• Percent Time Spent >300 mg/dL [Daytime [7am - 11pm]]: The percentage of time spent above 300 mg/dL during the Daytime period. CGM measured blood sugar values above 300 mg/dL are considered to be undesirable. Thus, less time spent above 300 mg/dL is considered a positive outcome.
• Mean Glucose [Daytime [7am - 11pm]]: Mean glucose is a measure of the average CGM value in mg/dL during the Daytime period. A lower value, without approaching hypoglycemia, is indicative of a desirable outcome.
• Glucose Variability [Daytime [7am - 11pm]]: Variability of glucose during the Daytime period
• Insulin [Daytime [7am - 11pm]]: Amount (U/kg) of insulin administered during the Daytime period
• CHO Treatment [Daytime [7am - 11pm]]: The amount of carbohydrates in grams administered as treatment for hypoglycemia in the Daytime period.
• Percent Time Spent <50 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent below 50 mg/dL during the Overnight period. CGM measured blood sugar values below 50 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 50 mg/dL is considered a better outcome.
• Percent Time Spent <54 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent below 54 mg/dL during the Overnight period. CGM measured blood sugar values below 54 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 54 mg/dL is considered a better outcome.
• Percent Time Spent <60 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent below 60 mg/dL during the Overnight period. CGM measured blood sugar values below 60 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 60 mg/dL is considered a better outcome.
• Percent Time Spent <70 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent below 70 mg/dL during the Overall period. CGM measured blood sugar values below 70 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 70 mg/dL is considered a better outcome.
• Percent Time Spent Between 70 and 150 mg/dL [Overnight [11pm - 7am]]: This outcome looks at the percentage of time spent between 70 and 150 mg/dL during the Overnight, defined as 11pm-7am.
• Percent Time Spent >180 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent above 180 mg/dL during the Overnight period. CGM measured blood sugar values above 180 mg/dL are considered to be undesirable. Thus, less time spent above 180 mg/dL is considered a positive outcome.
• Percent Time Spent >250 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent above 250 mg/dL during the Overnight period. CGM measured blood sugar values above 250 mg/dL are considered to be undesirable. Thus, less time spent above 250 mg/dL is considered a positive outcome.
• Percent Time Spent >300 mg/dL [Overnight [11pm - 7am]]: The percentage of time spent above 300 mg/dL during the Overnight period. CGM measured blood sugar values above 300 mg/dL are considered to be undesirable. Thus, less time spent above 300 mg/dL is considered a positive outcome.
• Mean Glucose [Overnight [11pm - 7am]]: Mean glucose is a measure of the average CGM value in mg/dL during the Overnight period. A lower value, without approaching hypoglycemia, is indicative of a desirable outcome.
• Glucose Variability [Overnight [11pm - 7am]]: Variability of glucose during the Overnight period
• Insulin [Overnight [11pm - 7am]]: Amount (U/kg) of insulin administered during the Overnight period
• CHO Treatment [Overnight [11pm - 7am]]: The amount of carbohydrates in grams administered as treatment for hypoglycemia in the Overnight period.
• Percent Time Spent <50 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent below 50 mg/dL during the Skiing period. CGM measured blood sugar values below 50 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 50 mg/dL is considered a better outcome.
• Percent Time Spent <54 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent below 54 mg/dL during the Skiing period. CGM measured blood sugar values below 54 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 54 mg/dL is considered a better outcome.
• Percent Time Spent <60 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent below 60 mg/dL during the Skiing period. CGM measured blood sugar values below 60 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 60 mg/dL is considered a better outcome.
• Percent Time Spent <70 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent below 70 mg/dL during the Skiing period. CGM measured blood sugar values below 70 mg/dL falls into the range of hypoglycemia which have the potential to lead to unconsciousness or death. Thus, less time below 70 mg/dL is considered a better outcome.
• Percent Time Spent >180 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent above 180 mg/dL during the Skiing period. CGM measured blood sugar values above 180 mg/dL are considered to be undesirable. Thus, less time spent above 180 mg/dL is considered a positive outcome.
• Percent Time Spent >250 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent above 250 mg/dL during the Skiing period. CGM measured blood sugar values above 250 mg/dL are considered to be undesirable. Thus, less time spent above 250 mg/dL is considered a positive outcome.
• Percent Time Spent >300 mg/dL [Skiing [9:30am-noon and 1:30pm-4pm]]: The percentage of time spent above 300 mg/dL during the Skiing period. CGM measured blood sugar values above 300 mg/dL are considered to be undesirable. Thus, less time spent above 300 mg/dL is considered a positive outcome.
• Mean Glucose [Skiing [9:30am-noon and 1:30pm-4pm]]: Mean glucose is a measure of the average CGM value in mg/dL during the Skiing period. A lower value, without approaching hypoglycemia, is indicative of a desirable outcome.
• Glucose Variability [Skiing [9:30am-noon and 1:30pm-4pm]: Variability of glucose during the Skiing period
• Insulin [Skiing [9:30am-noon and 1:30pm-4pm]]: Amount (U/kg) of insulin administered during the Skiing period
• CHO Treatment [Skiing [9:30am-noon and 1:30pm-4pm]]: The amount of carbohydrates in grams administered as treatment for hypoglycemia in the Skiing period.

Sex: All, ages: 6 Years to 18 Years

Inclusion Criteria:

1. Criteria for documented hyperglycemia (at least 1 must be met):

   * Clinical diagnosis of type 1 diabetes (C-peptide levels and antibody determinations are not required)
   * The diagnosis of type 1 diabetes is based on the investigator's judgment
2. Criteria for requiring insulin at diagnosis (both criteria must be met):

   * Daily insulin therapy for ≥ 6 months
   * Insulin pump therapy for ≥ 3 months (note: must be willing to disable any glucose suspend, predictive suspend, or artificial pancreas functionality on insulin pump during study)
3. Virginia camp: age 13-18 years; Colorado/Stanford camps: 6-12 years
4. Avoidance of acetaminophen-containing medications (i.e. Tylenol) while wearing the continuous glucose monitor.
5. Willingness to wear a continuous glucose sensor and physiological monitor for the duration of the study
6. Not being pregnant at the start of the trial. All female subjects of childbearing potential will be screened for pregnancy.

8\. If the participant is less than 13 years of age and the parents or the study team request it, at least one parent commit to stay with the study subject at the camp site 9. A parent/caregiver is available for system training and will commit to be the main responsible person for the use of the AP system at home

Exclusion Criteria:

1. Diabetic ketoacidosis in the past 6 months
2. Hypoglycemic seizure or loss of consciousness in the past 6 months
3. History of seizure disorder (except for hypoglycemic seizure)
4. History of any heart disease including coronary artery disease, heart failure, or arrhythmias
5. History of altitude sickness
6. Chronic pulmonary conditions that could impair oxygenation
7. Cystic fibrosis
8. Current use of oral glucocorticoids, beta-blockers or other medications, which in the judgment of the investigator would be a contraindication to participation in the study.
9. History of ongoing renal disease (other than microalbuminuria).
10. Subjects requiring intermediate or long-acting insulin (such as NPH, Detemir or Glargine).
11. Subjects requiring other anti-diabetic medications other than insulin (oral or injectable).
12. Pregnancy
13. Presence of a febrile illness within 24 hours of start ski camp or acetaminophen use while wearing the CGM. The camp study subject will not participate in the trial if these conditions are met.
14. Medical or psychiatric condition that in the judgment of the investigator might interfere with the completion of the protocol such as (for parent and/or child):

    * Inpatient psychiatric treatment in the past 6 months
    * Uncontrolled adrenal insufficiency
    * Alcohol abuse

Participant flow

Outcome results

• Percent Time Spent Between 70 and 180 mg/dL (Primary), Mean, percentage of time: Experimental AP Group 66.4 +/- 16.4; Control SAP Group 53.9 +/- 24.8 (p 0.010)
• Percent Time Spent Between 70 and 180 mg/dL (Primary), Mean, percentage of time: Experimental AP Group 62.4 +/- 18.8; Control SAP Group 54.8 +/- 24.9 (p 0.095)
• Percent Time Spent Between 70 and 180 mg/dL (Primary), Mean, percentage of time: Experimental AP Group 78.6 +/- 20.3; Control SAP Group 50.9 +/- 34.2 (p <0.001)
• Percent Time Spent Between 70 and 180 mg/dL (Primary), Mean, percentage of time: Experimental AP Group 57.8 +/- 27.3; Control SAP Group 55.9 +/- 31.1 (p >0.2)
• Percent Time Spent <50 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0); Control SAP Group 0 (0 to 0) (p >0.2)
• Percent Time Spent <54 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0); Control SAP Group 0 (0 to 0.1) (p >0.2)
• Percent Time Spent <60 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0.8); Control SAP Group 0 (0 to 0.6) (p >0.2)
• Percent Time Spent <70 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 2 (0.5 to 3.8); Control SAP Group 0.8 (0 to 3.7) (p >0.2)
• Percent Time Spent >180 mg/dL (Secondary), Mean, percentage of time: Experimental AP Group 31.4 +/- 17.6; Control SAP Group 43 +/- 24.5 (p 0.015)
• Percent Time Spent >250 mg/dL (Secondary), Mean, percentage of time: Experimental AP Group 10.4 +/- 11.4; Control SAP Group 16 +/- 13.6 (p 0.059)
• Percent Time Spent >300 mg/dL (Secondary), Mean, percentage of time: Experimental AP Group 3.9 +/- 5.9; Control SAP Group 6.9 +/- 6.7 (p 0.034)
• Mean Glucose (Secondary), Mean, mg/dL: Experimental AP Group 161 +/- 29.9; Control SAP Group 176.8 +/- 36.5 (p 0.023)
• Glucose Variability (Secondary), Mean, coefficient of variation: Experimental AP Group 34.2 +/- 6.1; Control SAP Group 33.9 +/- 8.4 (p >0.2)
• Insulin (Secondary), Mean, U/kg: Experimental AP Group 40.5 +/- 16.7; Control SAP Group 43.9 +/- 28.4 (p >0.2)
• Carbohydrate (CHO) Treatment (Secondary), Mean, grams: Experimental AP Group 45.5 +/- 27.8; Control SAP Group 57.7 +/- 57.8 (p >0.2)
• Percent Time Spent <50 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0); Control SAP Group 0 (0 to 0) (p >0.2)
• Percent Time Spent <54 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0); Control SAP Group 0 (0 to 0) (p >0.2)
• Percent Time Spent <60 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 0 (0 to 0.3); Control SAP Group 0 (0 to 0.1) (p >0.2)
• Percent Time Spent <70 mg/dL (Secondary), Median, percentage of time: Experimental AP Group 1 (0 to 3.3); Control SAP Group 0.8 (0 to 2) (p >0.2)
• Percent Time Spent >180 mg/dL (Secondary), Mean, percentage of time: Experimental AP Group 35.7 +/- 19.8; Control SAP Group 42.5 +/- 24.9 (p 0.124)
• 29 more outcome measures not shown.

Adverse events

Time frame: 48 hours

Limitations and caveats: Data for 3 participants were excluded. Subject 1: a software error resulted in prolonged AP system downline. The error was identified in data analysis; Subject 2: repeated pump occlusion resulted in prolonged system downtime; Subject 3: study pump initialized with siblings pump settings resulting in strong biased results.

• Results publication: Ekhlaspour L, Forlenza GP, Chernavvsky D, Maahs DM, Wadwa RP, Deboer MD, Messer LH, Town M, Pinnata J, Kruse G, Kovatchev BP, Buckingham BA, Breton MD. Closed loop control in adolescents and children during winter sports: Use of the Tandem Control-IQ AP system. Pediatr Diabetes. 2019 Sep;20(6):759-768. doi: 10.1111/pedi.12867. Epub 2019 May 23. PMID 31099946

• Study Protocol and Statistical Analysis Plan (PDF, 2018-01-02)
• Informed Consent Form (PDF, 2018-01-03)

• Marc Breton, PhD, Principal investigator, University of Virginia Center for Diabetes Technology