Dual-Hormone Closed-Loop Glucose Control in Adolescents With Type 1 Diabetes (DHCL2021)

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).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Glucagon; Device: Closed-loop System

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen
  • Herlev, Denmark, 2730
    • Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dual-hormone Closed-loop; FiAsp® and GlucaGen®.	Drug: Glucagon; Glucagon is filled in the pump and given automatically in case of hypoglycemia or pending hypoglycemia.; Other Names: GlucaGen, Novo Nordisk,; Device: Closed-loop System; 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.; Other Names: Saline
Placebo Comparator: Single-Hormone Closed-loop; FiAsp® and isotonic saline.	Device: Closed-loop System; 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.; Other Names: Saline

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Herlev Hospital; Technical University of Denmark

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2021
• Primary Completion (Actual): April 26, 2022
• Study Completion (Actual): April 26, 2022

Study Registration Dates

• First Submitted: May 18, 2021
• First Submitted That Met QC Criteria: June 24, 2021
• First Posted (Actual): July 2, 2021

Study Record Updates

• Last Update Posted (Actual): August 18, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: H-21000207; 2020-005836-31 (EudraCT Number); 2021-0409-34 (Other Identifier: Eudramed CIV-ID-nr.); PD002-19 (Other Grant/Funding Number: Danish Diabetes Academy)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: From 1 year to 10 years after completion
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No