Dual-hormone Closed-loop Glucose Control in Type 1 Diabetes (DHCL2019)

August 17, 2022 updated by: Steno Diabetes Center Copenhagen
Despite recent pharmacological and technological advantages, hypoglycemia remains to be the key limiting factor in achieving optimal glycemic control in people with type 1 diabetes. State-of-the-art treatment for type 1 diabetes is insulin in pens or pumps that focus on reducing hyperglycemia after relative insulin deficiency e.g. after food intake. In recent years, we focused on adding low-dose glucagon to insulin therapies for the treatment and prevention of hypoglycemia - referred to as "dual-hormone treatment". We have shown that low-dose glucagon is efficient in treating mild hypoglycemia and that several factors may affect its glucose response. Our next step is to test whether the combined delivery of insulin and glucagon can improve glucose control in individuals with type 1 diabetes. In this proposal, we want to test the efficacy, safety and feasibility of a dual-hormone closed-loop system, also known as an artificial pancreas. The closed-loop system involves automatic infusion of glucagon and insulin based on continuous glucose measurements. The system will be tested in a 33-hour in-clinic study comparing the glucose control by the combined automatic delivery of insulin and glucagon with the automatic delivery of insulin-only. The study is performed at Steno Diabetes Center Copenhagen (SDCC) in collaboration with the Technical University of Denmark (DTU). We expect that the study will clarify whether low-dose glucagon added to insulin therapy can improve the glucose control in adults with type 1 diabetes. We believe that the utilization of glucagon will allow for a weight neutral optimization of glucose control, reduce risk of hypoglycemia and reduce disease burden that will reduce diabetes complications and cardiovascular diseases.

Study Overview

Status

Completed

Detailed Description

Rationale: We hypothesize that our newly developed dual-hormone insulin-glucagon closed-loop system (DCL) is safe, efficient and superior to our single-hormone insulin-only closed-loop system (SCL). The study aims to compare the glucose control achieved by DCL with our SCL.

Design: A randomized single-blinded placebo-controlled cross-over 33-hour in-clinic study of glucose control achieved with DCL versus SCL in adults and adolescents with type 1 diabetes.

Participants: 13 insulin-pump treated T1D participants will be included, if they are 15-80 years old, have T1D for ≥ 3 years, use insulin pumps with FiAsp®, and have an HbA1c≤ 8.5% (69 mmol/mol).

Procedures: In this two-phase study 1) we test the operability of our closed-loop systems and 2) compare glucose control by DCL with SCL. The two studies are identical except for the blinding procedures. In the first phase (pilot study), four participants are included, and the glucagon/saline pump is not masked. In the second phase (main study), 13 participants are included, and are as well as the investigators blinded for the content in the glucagon/saline pump.

Two days prior to study visit, a CGM (Dexcom® G6) is place on the participant's abdomen. At study visits, participants arrive in the evening at our research unit and get their insulin pump disconnected. Two study pumps (Dana Diabecare RS®, SOOIL) are attached: one pump infuses insulin (FiAsp®, Novo Nordisk) and the other infuses either glucagon (GlucaGen®, Novo Nordisk) or saline. Once a sampling cannula is placed in an antecubital vein, the study is initiated and the closed-loop system (DCL vs SCL) takes over the glucose control for the next 33 hours. Except from the control algorithm (SCL vs DCL), the study days are identical. Participants can move around freely in the clinic for 33 hours but will perform a 45-min moderate (50% VO2max) exercise session, consume three meals with variant carbohydrate content, and sleep during two overnight periods. Participants will be monitored frequently with blood samples (drawn from the antecubital vein), blood pressure, pulse, and VAS scale for nausea.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Gentofte, Denmark
        • Steno Diabetes Center Copenhagen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria

  • Age ≥ 18 years
  • T1D ≥ 2 years
  • Insulin pump therapy ≥ 1
  • Currently treated with FiAsp® - insulin
  • HbA1c ≤ 8.5% (69 mmol/mol) Exclusion criteria
  • Pregnancy or nursing
  • Inability and willingness to comply with all protocol procedures, e.g. exercise, sleeping, blood sampling, and meal consumption
  • Plan to become pregnant or sexually active and not using adequate contraceptive methods (sterilization, intrauterine device, contraceptive pill, patch or injection)
  • Hypoglycemia unawareness (self-reported lack of hypoglycemia symptoms when blood glucose is < 3.0 mmol/l)
  • Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during or within 30 days prior to study participation
  • History of coronary artery disease or congestive heart failure
  • Abnormal ECG suggestive of coronary artery disease and increased risk of malignant arrhythmia
  • Allergy to glucagon or lactose
  • Pheochromocytoma
  • Other concomitant medical or psychological condition that according to the investigator's assessment makes the patient unsuitable for study participation

Withdrawal criteria

  • In case of pregnancy (or desire for pregnancy), female subjects are withdrawn
  • Lack of compliance to any of the important study procedures in the discretion of the investigator
  • Unacceptable adverse effects in the discretion of the investigator
  • Withdrawal on participants request will be accepted at any time without further justification

Patients who complete or withdraw from the study continue their usual quarterly follow-up visits at the diabetes clinic. Withdrawal does not affect their statutory patient rights.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Single-hormone
FiAsp (R) - Saline
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.
ACTIVE_COMPARATOR: Dual-hormone
FiAsp(R) - GlucaGen(R)
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.
GlucaGen(R), Novo Nordisk, DK

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 glucose sensor
Time Frame: 33 hours
33 hours
Number of carbohydrate interventions to treat hypoglycemia
Time Frame: 33 hours
Carbohydrate interventions are predefined and provided in case of hypoglycemia
33 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of time with glucose values < 3.9 mmol/l as measured by venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of participants achieving (A) time in range (3.9-10 mmol/l) > 70 %, (B) time in alert hypoglycemia (<3.9 mmol/l) < 4 %, and (C) time in clinical hypoglycemia (<3.0 mmol) < 1% as measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
A composite outcome will be calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Mean blood glucose value measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of time with glucose values in the range 3.9-8.0 mmol/l measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of time with glucose values in the range 3.9-10.0 mmol/l measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of time with glucose values in the range > 13.9 measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of time with glucose values < 3.0 mmol/l as measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Number of hypoglycemic episodes (<3.9 mmol/l and <3.0 mmol/l) overnight and during daytime
Time Frame: 33 hours
33 hours
Nadir blood glucose value for each hypoglycemic episode as measured by glucose sensor and venous plasma glucose
Time Frame: 33 hours
33 hours
Glucose sensor glycemic variability measured as SD and CV during overnight and during daytime
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Low Blood Glucose Index (LBGI) overnight and during daytime by glucose sensor and venous plasma glucose
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Percentage of participants with a mean blood glucose value (glucose sensor and venous plasma glucose) ≤ 8.6 mmol/l (corresponding to an estimated HbA1c of 7.0% / 53 mmol/mol)
Time Frame: 33 hours
33 hours
Percentage of patients with a mean blood glucose value (glucose sensor and venous plasma glucose) ≤ their standard therapy mean glucose value (calculated based on HbA1c measurement)
Time Frame: 33 hours
33 hours
Mean Absolute Relative Difference (MARD) between glucose sensor and venous plasma glucose
Time Frame: 33 hours
Participants have two glucose sensors during the study
33 hours
Percentages of values between glucose sensor and venous plasma glucose in zone A, B, C, D and E in the Clarke Error Grid analysis.
Time Frame: 33 hours
Participants have two glucose sensors during the study. One sensor closed to the infusion of glucagon.
33 hours
Mean blood pressure over the study period (mmHG)
Time Frame: 33 hours
Blood pressure and pulse taken at predefined timepoints
33 hours
Mean pulse rate over the study period (beats per min)
Time Frame: 33 hours
Blood pressure and pulse taken at predefined timepoints
33 hours
Mean nausea level measured with a visual analog scale (VAS range: 0-10)
Time Frame: 33 hours
Calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Total insulin dose per study day (UI)
Time Frame: 33 hours
33 hours
Total time of insulin suspension per study day (UI)
Time Frame: 33 hours
33 hours
Total glucagon dose per study day (microgram)
Time Frame: 33 hours
the outcome will be calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Mean plasma glucagon
Time Frame: 33 hours
the outcome will be calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Mean plasma insulin aspart
Time Frame: 33 hours
the outcome will be calculated for the whole study period as well as for the following intervals: night 1 (23:00-07:00), night 2 (23:00-07:00), night 1 and 2, 23:00-15:00 and 15:00-07:00.
33 hours
Difference in participant estimated grams of carbohydrate and actual carbohydrate in study meals
Time Frame: 33 hours
Meals presented at the study will be estimated for carbohydrate content by the participant on
33 hours
Difference in participant estimated blood glucose level and plasma glucose level at predefined timepoints
Time Frame: 33 hours
Self-assessment of glucose levels (Clarke Error Grid)
33 hours
Total energy expenditure during the study visit (kcal/kg) measured by ActiGraph GT9X Link
Time Frame: 33 hours
Freedson and Sasaki MET prediction equations to determine energy expenditure in MET
33 hours
Steps taken during the study visit measured by ActiGraph GT9X Link
Time Frame: 33 hours
33 hours
Minutes per study day (min/d) spent in different levels of activity (sedentary, light, moderate, vigorous, or MVPA) measured by ActiGraph GT9X Link
Time Frame: 45 min
45 min
Minutes between lights off and the first sleep episode (Sleep latency) measured by ActiGraph GT9X Link
Time Frame: 14 hours
14 hours
Total sleep time measured by ActiGraph GT9X Link
Time Frame: 14 hours
Minutes between sleep onset and wake time
14 hours
The percentage of time asleep from lights off to lights on (sleep efficiency) measured by ActiGraph GT9X Link
Time Frame: 14 hours
14 hours
Mean Borg scale level during exercise (RANGE:0-10)
Time Frame: 45 min
Assessed every 5-10 minutes during bicycling
45 min

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Ajenthen G Ranjan, MD, PhD, Steno Diabetes Center Copenhagen

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 16, 2019

Primary Completion (ACTUAL)

March 19, 2021

Study Completion (ACTUAL)

March 19, 2021

Study Registration Dates

First Submitted

August 8, 2019

First Submitted That Met QC Criteria

August 9, 2019

First Posted (ACTUAL)

August 12, 2019

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

Other Study ID Numbers

  • H-19026331
  • 2019-001631-31 (EUDRACT_NUMBER)
  • 2019043528 (REGISTRY: Danish Medical Agency)
  • 2019043269 (REGISTRY: Danish Medical Agency - Device regulation)
  • CIV-19-04-028465 (REGISTRY: CIV ID)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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