Closed-loop Insulin Delivery in the General Ward

Study Overview
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Brief Summary
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The study assesses the efficacy and safety of closed-loop glucose control in patients with insulin-treated type 2 diabetes. Phase 1 The study objective is to compare conventional insulin therapy with closed-loop glucose control combined with once daily basal insulin injection over 72 hours in hospitalised insulin treated T2D subjects. Phase 2 The study objective is to compare conventional insulin therapy with closed-loop glucose control up to maximum 15 days in hospitalised insulin treated T2D subjects. Phase 3 The study objective is to compare conventional insulin therapy with closed-loop glucose control applying faster insulin aspart up to maximum 15 days in insulin-treated inpatients receiving parenteral and/or enteral nutrition. Phase 4 The study objective is to compare automated closed-loop control using faster acting insulin aspart with closed-loop control using standard insulin aspart.

Detailed Description
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Hyperglycaemia in hospitalized patients is becoming a common clinical problem due to the increasing prevalence of diabetes mellitus . Hyperglycaemia in this cohort can also occur in patients with previously undiagnosed diabetes, or during acute illness in those with previously normal glucose tolerance. As a result, the prevalence of acute or stress hyperglycaemia in hospitalised patients has been widely reported. A growing body of evidence currently suggest that the degree of hyperglycaemia upon admission and the duration of hyperglycaemia during their illness are associated with adverse outcomes.In-patient hyperglycaemia is now widely recognised as a poor prognostic marker in terms of morbidity and mortality, increased length of stay and cost to the healthcare system. The current management of in-patient hyperglycaemia in non-critical care is still far from ideal, and vary widely between different centres. The discordance between clinical evidence and practice is due to a number of factors which could potentially undermine patient care and safety. Of these, hypoglycaemia remains one the biggest barriers to managing in-patient hyperglycaemia. There is therefore a need to develop and validate a more effective and safer system to manage in-patient hyperglycaemia. A closed-loop insulin infusion system has previously been tested and reported to be feasible and safe in intensive care patients. Its utilisation in non-critical patients in the general medical and surgical wards currently remains unproven. Its use in this cohort however could potentially be of significant practical and clinical value, especially in a busy ward environment. The Model Predictive Control (MPC) algorithm developed by our group at the University of Cambridge utilises fundamental glucoregulatory processes and predicts future glucose excursion resulting from projected insulin infusion rates. The algorithm can also account for the patient's meal intake and the duration of action of the short acting insulin used. This has the distinct advantage over the reactive approach of sliding scale insulin protocols, which treats hyperglycaemia after it has already occurred. The MPC algorithm has been studied in intensive care and cardiac surgery patients, and results from these studies to date have been encouraging. It is shown to be associated with a significantly higher percentage of time within the blood glucose target range, without increasing the risk of severe hypoglycaemia. The expectant role of a closed-loop system using the MPC algorithm in non-critical care patients would therefore be to provide clinicians with an effective and safe method to manage hyperglycaemia in hospital. In early 2017, faster-acting insulin aspart (Fiasp, Novo Nordisk, Copenhagen, Denmark) received marketing authorisation from the European Commission. Due to the more favourable pharmacokinetic profile, Fiasp has the potential to further improve safety and efficacy of fully automated closed-loop glucose control.

Official Title
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A Randomised Study to Assess the Efficacy and Safety of Automated Closed-loop Glucose Control in Insulin Treated Type 2 Diabetes (Phase 1), Inpatient Hyperglycaemia Requiring Subcutaneous Insulin Therapy (Phase 2 and Phase 3) and to Evaluate Use of Closed-loop Applying Faster Insulin Aspart Versus Standard Insulin Aspart (Phase 4)

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Device: Fully Automated Closed-Loop Insulin Delivery
* Device: Conventional insulin therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older Type 2 Diabetes for at least 1 year as defined by WHO (phase 1 and 4) Inpatient hyperglycaemia requiring subcutaneous insulin therapy (phase 2 and 3) Treatment with subcutaneous insulin alone or in combination with oral glucose-lowering medication(s) (phase 4: basal bolus insulin regime for at least 3 months) Receiving parenteral and/or enteral nutrition (phase 3) HbA1c<11.0% (phase 4) Exclusion Criteria: Autoimmune type 1 diabetes Known or suspected allergy against insulin Known proliferative retinopathy Current or planned pregnancy or breast feeding Unstable or end-stage cardiac and renal disease (phase 1 only) Planned surgery during study period (phase 1 only) Current in-patient in intensive care unit Any physical or psychological disease or medication(s) likely to interfere with the conduct of the study and interpretation of the study results, as judged by the study clinician Likely discharge earlier than 72 hours (phase 1 only)

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Interventional Model Description: Randomised parallel (phase 1-3) and randomised crossover (phase 4)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fully Automated Closed-Loop Insulin Delivery (phase 1-4)<br>The control algorithm will automatically direct between meals and meal-related subcutaneous insulin delivery utilizing real-time continuous glucose monitoring (RT-CGM) data. The subcutaneous insulin pump will deliver insulin Aspart or similar. In phase 1, a once daily basal insulin analogue will also be given subcutaneously at 20% the patient's usual total daily dose. In phase 3 and 4 faster-acting insulin aspart (Fiasp) is applied. | Device: Fully Automated Closed-Loop Insulin Delivery<br> <br> |
| Active Comparator: Usual care/ fully-automated closed-loop using Iasp<br>Phase 1-3: During usual care (conventional therapy), subject's s.c. insulin dose and regimen on admission will be adjusted as necessary by the clinical team according to local centres' usual clinical practice. Subjects will have masked CGM sensors inserted during the study (CGM readings will be masked throughout the study). Phase 4: subjects will receive fully-automated insulin delivery using standard insulin aspart (Iasp) | Device: Conventional insulin therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time spent in target glucose range (5.6-10.0mmol/l) | Primary outcome will be measured using continuous subcutaneous glucose monitoring (CGM) data (Phase 1-3) and plasma (Phase 4). | Phase 1 (Pilot study) = 72-hours, Phase 2 (Follow-up study) = Up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of time with glucose levels below 5.6 mmol/l and above 10.0 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 1 (Pilot study) = 72-hours, Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4=between 07:00 and 17:00 | 
| Average glucose levels, as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 1 (Pilot study) = 72-hours, Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4=between 07:00 and 17:00 | 
| Proportion of time with glucose levels below 3.9 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 1 (Pilot study) = 72-hours, Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4=between 07:00 and 17:00 | 
| Proportion of time with glucose levels below 3.0 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4= over 10 hours | 
| Proportion of time with glucose levels below 2.8 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4= over 10 hours | 
| Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 1 (Pilot study) = 72-hours, Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Area under the curve of sensor glucose levels below 3.0 mmol/l as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Standard deviation and coefficient of variation of glucose levels, as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 1 (Pilot study) = 72-hours, Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Proportion of time with glucose levels in significant hyperglycaemic range (>20mmol/l) as recorded by CGM | CGM (Phase 1-4) and plasma glucose (Phase4) | Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Total daily insulin dose |  | Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Between 24 hour period variability | Coefficient of variation of CGM glucose between 24 hour periods (08:00 to 08:00) (Phase 1-3) | Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Number of capillary glucose confirmed hypoglycaemic events <3.5mmol/l | Capillary glucose measurements will be performed using hospital point of care devices | Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours | 
| Pre-breakfast, pre-lunch, pre-dinner, and evening capillary glucose values | Capillary glucose measurements will be performed using hospital point of care devices (Phase 1-3) | Phase 2-3 (Follow-up study) = Up to 15 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Insulin, Closed-Loop, Real-time CGM, Subcutaneous insulin pump, Hospital