Dual Hormone Closed Loop in Type 1 Diabetes (DARE)

• ClinicalTrials.gov Identifier: NCT05669547
• Recruitment Status: Not yet recruiting
• First Posted: January 3, 2023
• Last Update Posted: June 9, 2023
• Sponsor: UMC Utrecht
• Collaborators: Dutch National Health Care Institute; Inreda Diabetic B.V.
• Information provided by (Responsible Party): H.W. (Harold) de Valk, MD, PhD, UMC Utrecht

Study Description

Brief Summary:

This study is a 12 month open-label, two-arm randomised parallel-group trial in adult type 1 diabetes patients executed in 14 centres in the Netherlands. The aim of this study is to determine the long-term clinical effectiveness of treatment with a dual-hormone (insulin and glucagon) fully closed loop system during 12 months compared to the current most used care and to the currently most advanced technological care. Secondary objectives include the assessment of cost-effectiveness, Patient Reported Outcome Measures (PROMs), other glycaemic outcomes and safety.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1; Diabetes type1; Diabetes	Device: dual hormone fully closed loop (DHFCL)	Not Applicable

Detailed Description:

Rationale: Patients with type 1 diabetes mellitus (T1DM) require lifelong insulin therapy. Insulin therapy improves but does not fully normalise blood glucose levels with current therapies. Current therapies include subcutaneous insulin injection or subcutaneous insulin infusion, combined with a device to measure glucose levels (finger stick, intermittent sensor or continuous glucose monitoring). Although having provided a huge improvement in glycaemic control, patients have to work hard every day and still have to calculate mealtime boluses. An automated insulin delivery device covering both basal and prandial insulin requirement would mean another great leap forwards. The dual-hormone fully closed loop (DHFCL) provides such a new strategy of automated insulin delivery coupled with targeted glucagon infusion as insulin-antagonist to even more approximate normal physiology.

Objective: To determine the long-term clinical effectiveness of treatment with a dual-hormone (insulin and glucagon) fully closed loop system during 12 months compared to the current most used care and to the currently most advanced technological care. Secondary objectives include the assessment of cost-effectiveness, Patient Reported Outcome Measures (PROMs), other glycaemic outcomes and safety.

Study design: A 12 month open-label, two-arm randomised parallel-group trial. Study population: Adult (age ≥18 years) patients with T1DM for at least 1 year with an HbA1c at entry ≤ 91 mmol/mol.

Intervention: The study includes two separately randomised arms, defined by current diabetes treatment. In one arm, patients currently on Multiple Daily Injections (MDI; at least once daily long-acting insulin and thrice daily short-acting insulin) in combination with continuous or flash glucose monitoring (CGM or FGM; currently the most used strategy) are 1:1 randomised to either the intervention, i.e. the DHFCL, or continuation of their current treatment. In the other arm, patients currently on hybrid closed loop treatment (HCL; presently the most advanced diabetes control treatment) are 1:1 randomised to either the intervention or continuation of their current care.

Main study parameters/endpoints: The main study endpoint is the Time in Range (TIR; % of time spent in the 3.9-10 mmol/l target range) at 12 months, which will be compared between the intervention and the control treatment within each arm. Secondary endpoints include cost-effectiveness, PROMs, other glycaemic outcomes, safety measures and device-related outcomes.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Dual Hormone Closed Loop in Type 1 Diabetes: a Randomized Trial (DARE)
• Estimated Study Start Date: July 1, 2023
• Estimated Primary Completion Date: February 1, 2024
• Estimated Study Completion Date: December 1, 2024

Arms and Interventions

Arm	Intervention/treatment
No Intervention: Control; Patients currently on multiple daily injections (MDI) + continuous or flash glucose monitoring (CGM; FGM) or on a hybrid closed loop (HCL).
Experimental: Intervention; Patients on dual hormone fully closed loop (DHFCL) therapy.	Device: dual hormone fully closed loop (DHFCL); dual hormone fully closed loop consisting of an algorithm, sensors and both insulin and glucagon infusion.; Other Name: Inreda AP (Inreda Diabetic BV)

Outcome Measures

Primary Outcome Measures :

1. Time in Range (TIR) at 12 months (measured with an independent FSL Pro IQ sensor) [ Time Frame: 12 months ]
   TIR (% of time spent in the 3.9-10 mmol/l target range) at 12 months, which will be compared between the intervention and the control treatment within each arm.

Secondary Outcome Measures :

1. World Health Organization-Five Well-Being Index (WHO-5) score (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   The World Health Organisation- Five Well-Being Index (WHO-5) is a short self-reported measure of current mental wellbeing.
2. Health-related quality of life scores (EQ-5D-5L) (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   As described on the Euroqol website, the EQ-5D-5L measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression.
3. Problem Areas In Diabetes (PAID-5) score (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   Evaluates problem areas in diabetes
4. Diabetes Treatment and Satisfaction Questionnaire status and change (DTSQ-s and DTSQ-c) scores (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   Measurement of treatment satisfaction
5. Hypoglycaemia Fear Survey-II (HFS-II) Worry subscale score; (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   Measures hypoglycaemia fear
6. Pittsburgh Sleep Quality Index score (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   Measures sleep quality and duration
7. Insulin delivery systems: perceptions, ideas, reflections and expectations (INSPIRE) scores (Patient reported outcomes (PROMs) [ Time Frame: at 0, 3, 6, 9 and 12 months ]
   Measures ideas, perceptions and expectations of the insulin device - only for HCL (control) and DHFCL groups
8. Hypoglycaemia unawareness (Gold-Clarke) (Patient reported outcomes (PROMs) [ Time Frame: at 0 and 12 months ]
   Measurement of hypoglycaemia unawareness
9. Cost-effectiveness: cost per quality adjusted life year. [ Time Frame: 12 months ]

   To determine the cost-effectiveness of treatment with the DHFCL. Including data:

   Medical Consumption Questionnaire (MCQ), at 0, 3, 6, 9 and 12 months; Productivity Cost Questionnaire (PCQ), at 0, 3, 6, 9 and 12 months; Detailed hospital health care consumption for each individual patient (collected from electronic patient files, including unplanned contact moments) Cost effectiveness: cost per quality adjusted life year.

10. Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]
    Including Time Below Range (TBR), Time Above Range (TAR), glycaemic variability, number of hypoglycemic events and HbA1c.
11. Time Above Range (TAR) Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]

    Measured with an independent Freestyle Libre Pro IQ sensor

    • level 1 and 2 hyperglycaemia: >10.0 mmol/l;
    • level 2 hyperglycaemia: >13.9 mmol/l;
12. Time Below Range (TBR) Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]

    Measured with an independent Freestyle Libre Pro IQ sensor

    • level 1 and 2 hypoglycaemia: <3.9 mmol/l;
    • level 2 hypoglycaemia: <3.0 mmol/l;
13. Number of hypoglycaemic events Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]
    Measured with an independent Freestyle Libre Pro IQ sensor defined as glucose <3.0 mmol/l for 15 consecutive minutes when the time between two successive events is less than 30 minutes, they will be combined and counted as one event
14. Mean glucose Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]

    Measured with an independent Freestyle Libre Pro IQ sensor

    • day and night;
    • day: from 06:00 to 23:59 hours;
    • night: from 00:00 to 05:59 hours;
15. Glycaemic variability Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]

    Based on independent Freestyle Libre Pro IQ sensor data

    • Coefficient of variation;
    • Standard deviation.
16. HbA1c Other glycaemic outcomes [ Time Frame: at 0, 3, 6, 9 and 12 months ]

    venipuncture

    • Mean;
    • Percentage patients achieving HbA1c ≤ 53 mmol/mol.
17. Long-term safety outcomes [ Time Frame: 12 months ]
    To assess long-term safety of the DHFCL, including the incidence of (severe) adverse events, incidence of device issues and the effects of excluding daily use of acetaminophen on non steroidal inflammatory drug (NSAIDs) use and associated drug complications rate.
18. Daily insulin use (units/day) DHFCL outcomes [ Time Frame: at 3, 6, 9 and 12 months ]
    Measured by DHFCL device
19. daily glucagon use.DHFCL outcomes [ Time Frame: at 3, 6, 9 and 12 months ]
    Measured by DHFCL device Daily insulin use, daily glucagon use and percentage of time glucose control algorithm active at 0, 3, 6, 9 and 12 months.
20. Percentage of time glucose control algorithm active DHFCL outcomes [ Time Frame: at 3, 6, 9 and 12 months ]
    Measured by DHFCL device

Other Outcome Measures:

1. Patient reported daily insulin use control group [ Time Frame: at 3, 6, 9 and 12 months ]
   The amount of daily insulin use reported by the patients in the control group
2. Weight (kg) at baseline and 12 months [ Time Frame: 12 months ]
   Change of weight 0-12 months
3. Blood pressure (SBP/DBP in mmHg) at baseline and 12 months [ Time Frame: 12 months ]
   Change of blood pressure and heart rate 0-12 months
4. Heart rate (/min) at baseline and 12 months [ Time Frame: 12 months ]
   Change of heart rate 0-12 months
5. Frequency of unplanned patient contact with the diabetes team [ Time Frame: at 3, 6, 9 and 12 months ]
   Evaluating whether the DHFCL imposes more unplanned patient contact moments
6. Concomitant medication, at screening, baseline, 3, 6, 9 and 12 months [ Time Frame: at screening, baseline, 3, 6, 9 and 12 months ]
   Evaluation of medication
7. Continuation rate of the DHFCL [ Time Frame: at 12 months ]
   Expressed as the percentage of participants that continue DHFCL treatment after 1 year of use
8. Reasons for discontinuation of the DHFCL treatment. [ Time Frame: at 3, 6, 9 and 12 months ]
   Patients will be asked by the physician what the reason of discontinuation is when discontinuing the DHFCL treatment before the end of study

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age between 18 and 75 years;
• Diagnosed with type 1 diabetes mellitus at least one year ago;
• HbA1c ≤ 91 mmol/mol;

• Treated with either MDI with FGM/CGM or treated with HCL:

  • MDI+FGM/CGM for ≥ 3 months with an adequate sensor use during at least 70% of the time in the month prior to screening (based on sensor usage from the download summary report of the FGM/CGM);
  • HCL for ≥ 3 months with a frequency of use ≥ 70% of the time in auto mode over the previous month prior to screening;

• Does not reach the treatment goals over the last 8 weeks:

  • for MDI+FGM/CGM: subject has a TIR <80% or Time Below Range (TBR) >4%;
  • for HCL: subject has a TIR <80% or TBR >4%;
• Willing to take or switch to insulin Humalog when randomized to the intervention DHFCL arm;
• Under treatment in one of the participating centres;
• Willing and able to sign informed consent;
• Access to internet at home (for DHFCL data upload).

Exclusion Criteria:

• Current use of non-approved HCL device;
• BMI >35 kg/m2;
• eGFR<30 mL/min/1.73m2;
• Plan to change usual diabetes regimen in the next 3 months;
• Current participation in another diabetes-related clinical trial;
• Actively participating in an investigational study (drug or device) wherein he/she has received treatment from an investigational study drug or device in the last 2 weeks before enrolment into this study, as per investigator judgment;
• Established history of allergy or severe reaction to adhesive or tape that must be used in the study;
• Use of oral glucose-lowering medication;
• Active retinopathy or painful neuropathy;
• Daily use of acetaminophen during the trial (all arms), as this may influence the sensor glucose measurements. Incidental use with a maximum of e.g. 3 daily doses of 1000mg paracetamol for a maximum of 3 consecutive days is allowed
• Limited ability to see, and to hear or feel alarm signals of the closed loop system;
• Current pregnancy, breast feeding or planning to become pregnant in the 12 months of the trial or using ineffective birth control methods;
• Presence of a medical or psychiatric condition, longstanding serious adherence problems, anticipated problems in handing over diabetes control to a device or use of a medication that, in the judgment of the investigator, clinical protocol chair, or medical monitor, could compromise the results of the study or the safety of the participant.

Contacts and Locations

Contacts

Contact: Milena Jancev, MD; +31 88 75 5555; m.jancev-3@umcutrecht.nl

Contact: Harold de Valk, MD, PhD; +31 88 75 5555; H.W.deValk@umcutrecht.nl

Locations

Netherlands

Meander MC

Amersfoort, Netherlands

Contact: Meander MC

Principal Investigator: L.T. Dijkhorst-Oei, dr.

Amsterdam UMC, AMC

Amsterdam, Netherlands

Contact: Amsterdam UMC AMC

Principal Investigator: S.E. Siegelaar, dr.

Amsterdam UMC, VUmc

Amsterdam, Netherlands

Contact: Amsterdam UMC VUmc

Principal Investigator: E. Serne, dr.

OLVG

Amsterdam, Netherlands

Contact: OLVG Amsterdam

Principal Investigator: C.B. Brouwer, dr.

Gelre Ziekenhuis

Apeldoorn, Netherlands

Contact: Gelre Ziekenhuis

Principal Investigator: T. van Bemmel, dr.

Rijnstate

Arnhem, Netherlands

Contact: Rijnstate Ziekenhuis

Principal Investigator: A.C. van Bon, dr.

Jeroen Bosch Ziekenhuis

Den Bosch, Netherlands

Contact: Jeroen Bosch Ziekenhuis

Principal Investigator: F.A.W. Kemperman, dr.

Catharina Ziekenhuis

Eindhoven, Netherlands

Contact: Catharina Ziekenhuis

Principal Investigator: M.M. Oosterwerff, dr.

Martini Ziekenhuis

Groningen, Netherlands

Contact: Martini Ziekenhuis

Principal Investigator: K. Hoogenberg, dr.

UMC Groningen

Groningen, Netherlands

Contact: UMC Groningen

Principal Investigator: P.R. van Dijk, dr.

Tergooi Ziekenhuis

Hilversum, Netherlands

Contact: Tergooi Ziekenhuis

Principal Investigator: E. Seebus, dr.

St. Antonius

Nieuwegein, Netherlands

Contact: St. Antonius

Principal Investigator: L.P. Klieverik, dr.

UMC Utrecht

Utrecht, Netherlands

Contact: UMC Utrecht

Principal Investigator: H.W. de Valk, dr.

Isala Klinieken

Zwolle, Netherlands

Contact: Isala Klinieken

Principal Investigator: T.M. Vriesendorp

Sponsors and Collaborators

UMC Utrecht

Dutch National Health Care Institute

Inreda Diabetic B.V.

More Information

Additional Information:

DARE trial website (Dutch) 

• Responsible Party: H.W. (Harold) de Valk, MD, PhD, Principal Investigator, UMC Utrecht
• ClinicalTrials.gov Identifier: NCT05669547
• Other Study ID Numbers: 22/671
• First Posted: January 3, 2023
• Last Update Posted: June 9, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by H.W. (Harold) de Valk, MD, PhD, UMC Utrecht:

dual hormone; fully closed loop; bihormonal pump; artificial pancreas

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs