Dual-Hormone Closed-Loop Glucose Control in Adolescents With Type 1 Diabetes

Study Overview
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Brief Summary
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Objective: To assess the efficacy and safety of an insulin-glucagon dual-hormone (DH) closed-loop system compared with an insulin-only single-hormone (SH) closed-loop system in adolescent with type 1 diabetes. Methods: In a 26-h, randomized, crossover, inpatient study, 20 children and adolescents with type 1 diabetes used two modes of the DiaCon Artificial Pancreas system: DH and SH closed-loop control. During each study period, participants will have one overnight stay, received three meals and performed exercise for 45 min (bicycle with estimated 50% V02max). Endpoint: The primary endpoint is sensor-derived percentage of time in hypoglycemia (<3.9 mmol/L).

Detailed Description
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Upon arrival at the research facility at Steno Diabetes Center Copenhagen, the participant's own pump and CGM are disconnected, and the two study pumps are attached. For dual-hormone control, the study pumps will be filled with FiAsp® and GlucaGen®. For single-hormone control, the study pumps have been filled with FiAsp® and isotonic saline. In addition, participants are provided with a blinded wearable activity and sleep monitoring device (ActiGraph GT9X Link, Pensacola, FL) for activity level estimation and sleep assessment during study participation. The Actigraph is connected to a Bluetooth® Polar heart rate monitors during the exercise session. Female participants deliver a urine sample for pregnancy testing. A sampling cannula is placed in an antecubital vein. The CGM will be calibrated with fingerpick glucose meter (Contour next®, Ascensia Diabetes Care) before initiating the closed-loop control. Even though it is not needed to calibrate the sensor, the accuracy of the sensor is better after one calibration. At day 1 17:00 the study is initiated, and the closed-loop system takes over glucose control. Except from the control approach (single- vs. dual-hormone), the study days are identical. During the study visit, participants can move around freely, but they can only perform actual exercise during the stationary bike exercise session at day 2 16:30. At nighttime, the participants are encouraged to be in bed and, if possible, sleep. At predefined timepoints, the investigators measure blood pressure and pulse, and the investigators ask the participants to rate their nausea level on a visual analog scale (VAS) from 1 to 100 to assess possible side effects of glucagon (vomiting rates as 100). In addition, the investigators ask them to self-rate blood glucose levels before bedtime (23:00), upon wake-up (07:00-08:00), before each meal, before exercise, and every 10 minutes during exercise. Single-hormone and dual-hormone closed-loop control study sessions end 26 hours after study start. The study pumps and the CGMs are disconnected and the participants reconnect their own pumps and CGMs. The two study sessions are separated by at least 36 hours.

Official Title
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Dual-Hormone Closed-Loop Glucose Control in Adolescents With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Glucagon
* Device: Closed-loop System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age = 13-17 years T1D duration ≥ 2 years Insulin pump therapy ≥ 1 year Using CGM or isCGM (Flash Libre) HbA1c ≤ 9.0% (75 mmol/mol) Using carbohydrate counting Exclusion Criteria: Allergy to glucagon or lactose Allergy to faster insulin aspart (FiAsp) Pheochromocytoma Self-reported lack of hypoglycemia symptoms when blood glucose is < 3.0 mmol/l Inability to follow study procedures, e.g. exercise, sleeping, blood sampling, and meal intake Pregnancy, nursing, plan to become pregnant or sexually active and not using adequate contraceptive methods (intrauterine device, contraceptive pill, patch or injection) Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during or within 30 days prior to study participation Other concomitant medical or psychological condition that according to the investigator's assessment makes the participant unsuitable for study participation

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A randomized, single-blinded, cross-over study of glycemic control during dual-hormone therapy compared with single-hormone therapy in adolescents with type 1 diabetes.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dual-hormone Closed-loop<br>FiAsp® and GlucaGen®. | Drug: Glucagon<br>* Glucagon is filled in the pump and given automatically in case of hypoglycemia or pending hypoglycemia.<br>* Other names: GlucaGen, Novo Nordisk,;Device: Closed-loop System<br>* Closed-loop system comprise of two DANA RS (R) insulin pumps (FiAsp-GlucaGen vs FiAsp-saline), one DexCom G6 sensor, and a smartphone for the control algorithm.<br>* Other names: Saline;|
| Placebo Comparator: Single-Hormone Closed-loop<br>FiAsp® and isotonic saline. | Device: Closed-loop System<br>* Closed-loop system comprise of two DANA RS (R) insulin pumps (FiAsp-GlucaGen vs FiAsp-saline), one DexCom G6 sensor, and a smartphone for the control algorithm.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time with glucose values < 3.9 mmol/l as measured by the continuous glucose monitor | Percentage | 26 hours during closed-loop control | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of carbohydrate interventions to treat hypoglycemia |  | 26 hours during closed-loop control | 
| Percentage of time with glucose values in the range 3.9-10.0 mmol/l measured by continuous glucose monitor and plasma glucose | Percentage | 26 hours during closed-loop control | 
| Percentage of time with glucose values < 3.9 mmol/l as measured by plasma glucose | Percentage | 26 hours during closed-loop control | 
| Percentage of time with glucose values in the range > 13.9 mmol/l measured by continuous glucose monitor and plasma glucose | Percentage | 26 hours during closed-loop control | 
| Percentage of time with glucose values < 3.0 mmol/l as measured by continuous glucose monitor and plasma glucose | Percentage | 26 hours during closed-loop control | 
| Mean blood glucose value measured by continuous glucose monitor and plasma glucose | mmol/L | 26 hours during closed-loop control | 
| Number of hypoglycemic episodes < 3.9 mmol/l on continuous glucose monitor and plasma glucose | No. | 26 hours during closed-loop control | 
| Continuous glucose monitored glycemic variability measured as SD | mmol/L | 26 hours during closed-loop control | 
| Continuous glucose monitored glycemic variability measured as CV | percentage | 26 hours during closed-loop control | 
| Composite outcome: Percentage of participants achieving (1) time in range (3.9-10) > 70 %, (2) time in alert hypoglycemia (<3.9 mmol/l) < 4 %, and (3) time in clinical hypoglycemia (<3.0 mmol) < 1% as measured by CGM and YSI | percentage | 26 hours during closed-loop control | 
| Total insulin dose | units | 26 hours during closed-loop control | 
| Total glucagon dose | mg | 26 hours during closed-loop control | 
| Number of manual insulin boluses | No. | 26 hours during closed-loop control | 
| Number of adverse events - Nausea | No of event if visual analog scale (0-100) increase >10 from baseline | 26 hours during closed-loop control | 
| Number of adverse events - Headache | No of event if visual analog scale (0-100) increase >10 from baseline | 26 hours during closed-loop control | 
| Number of adverse events - Palpitation | No of event if visual analog scale (0-100) increase >10 from baseline | 26 hours during closed-loop control | 
| Number of vomits | No of event if visual analog scale (0-100) increase >10 from baseline | 26 hours during closed-loop control | 
| Difference between actual and participant-estimated carbohydrate content in meals | g per meal | 26 hours of closed-loop glucose control | 
| Mean Borg scale | Scale of perceived exertion from 6 (no effort activity) to 20 (max effort activity) | During 45 minutes exercise | 
| Physical activity intensity measured by ActiGraph GT9X Link | Percentage of sedentary activity | 26 hours | 
| Sleep efficiency measured by ActiGraph GT9X Link | The ratio of total sleep time to time in bed | 26 hours |