Closed-loop Insulin Delivery in the General Ward

Diabetes Mellitus Clinical Trial

— ANGIE02  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01774565
• Other study ID #: ANGIE02
• Secondary ID: A092763
• Status: Completed
• Phase: N/A
• Start date: August 2016
• Est. completion date: September 21, 2018

Study information

• Verified date: October 2018
• Source: University of Cambridge
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: September 21, 2018
• Est. primary completion date: September 21, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Diabetes Mellitus

Intervention

Device:
• Fully Automated Closed-Loop Insulin Delivery

• Conventional insulin therapy

Locations

Country	Name	City	State
Switzerland	Inselspital, Bern University Hospital, University of Bern, Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism	Bern
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge

Sponsors (3)

Lead Sponsor	Collaborator
University of Cambridge	Cambridge University Hospitals NHS Foundation Trust, University Hospital Inselspital, Berne

Countries where clinical trial is conducted

Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overnight period: Proportion of time with Glucose levels in target range (5.6-10.0mmol/l) as recorded by CGM	Between 24:00 and 08:00	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Overnight period: Average glucose levels, as recorded by CGM	Between 24:00 and 08:00	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Overnight period: Standard deviation and coefficient of variation of glucose levels, as recorded by CGM	Between 24:00 and 08:00	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Overnight period: Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM	Between 24:00 and 08:00	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Between night variability	Coefficient of variation of CGM glucose between nights (24:00 and 08:00 ) (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Total insulin dose overnight	Closed-loop only (24:00 and 08:00 ) (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Day period: Proportion of time with glucose levels in target range (5.6-10.0mmol/l) as recorded by CGM	Between 08:00 and 24:00 (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 day
Other	Day period: Average glucose levels, as recorded by CGM	Between 08:00 and 24:00 (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 day
Other	Day period: Standard deviation and coefficient of variation of glucose levels, as recorded by CGM	Between 08:00 and 24:00 (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 day
Other	Day period: Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM	Between 08:00 and 24:00 (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 day
Other	Between day variability	Coefficient of variation of CGM glucose between days (08:00 and 24:00 ) (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 day
Other	Total insulin dose during the day	Closed-loop only (08:00 and 24:00 ) (Phase 1-3)	Phase 2-3 (Follow-up study) = Up to 15 days
Other	Safety: Number of subjects and number of occurences of severe hypoglycaemic events (capillary glucose <2.2mmol/l)		Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
Other	Safety: Significant hyperglycaemic events (capillary glucose >20mmol/l) with or without ketonaemia (B-OHB >0.6mmol/l)		Phase 2 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
Other	Safety: Number of other (serious) adverse events (including adverse device effects) and device deficiencies		Phase 2 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
Other	2-hour postprandial incremental plasma glucose (Phase 4 only)	CGM and plasma glucose	120min after meal intake
Other	Peak glucose (Phase 4 only)	CGM and plasma glucose	over 10 hours
Other	Mean insulin concentration (Phase 4 only)	Plasma insulin concentration	over 10 hours
Other	Time to maximal insulin concentration (Phase 4 only)	Time (min) to maximal plasma insulin concentration	over 10 hours
Other	Maximal insulin concentration (Phase 4 only)	Maximal plasma insulin concentration	over 10 hours
Other	Total and endogenous insulin exposure within 1 hour postprandial period (Phase 4 only)	Total and endogenous plasma insulin exposure within 1 hour post-meal (iAUC)	over 10 hours
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Total daily insulin dose		Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
Secondary	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
Secondary	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
Secondary	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