Clinical trial NCT01774565: Closed-loop Insulin Delivery in the General Ward
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus
Keywords: Diabetes
Insulin
Closed-Loop
Real-time CGM
Subcutaneous insulin pump
Hospital
Lead sponsor: University of Cambridge
Sponsor class: OTHER
Collaborators: name: Cambridge University Hospitals NHS Foundation Trust
name: Insel Gruppe AG, University Hospital Bern
First posted: 2013-01-24
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised parallel (phase 1-3) and randomised crossover (phase 4)
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Time spent in target glucose range (5.6-10.0mmol/l)
timeFrame: Phase 1 (Pilot study) = 72-hours, Phase 2 (Follow-up study) = Up to 15 days
Secondary outcomes:
measure: Proportion of time with glucose levels below 5.6 mmol/l and above 10.0 mmol/l as recorded by CGM
timeFrame: 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
measure: Average glucose levels, as recorded by CGM
timeFrame: 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
measure: Proportion of time with glucose levels below 3.9 mmol/l as recorded by CGM
timeFrame: 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
measure: Proportion of time with glucose levels below 3.0 mmol/l as recorded by CGM
timeFrame: Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4= over 10 hours
measure: Proportion of time with glucose levels below 2.8 mmol/l as recorded by CGM
timeFrame: Phase 2 and Phase 3 (Follow-up study)= Up to 15 days, Phase 4= over 10 hours
measure: Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM
timeFrame: Phase 1 (Pilot study) = 72-hours, Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Area under the curve of sensor glucose levels below 3.0 mmol/l as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Standard deviation and coefficient of variation of glucose levels, as recorded by CGM
timeFrame: Phase 1 (Pilot study) = 72-hours, Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Proportion of time with glucose levels in significant hyperglycaemic range (>20mmol/l) as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Total daily insulin dose
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Between 24 hour period variability
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Number of capillary glucose confirmed hypoglycaemic events <3.5mmol/l
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4= over 10 hours
measure: Pre-breakfast, pre-lunch, pre-dinner, and evening capillary glucose values
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
Other outcomes:
measure: Overnight period: Proportion of time with Glucose levels in target range (5.6-10.0mmol/l) as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Overnight period: Average glucose levels, as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Overnight period: Standard deviation and coefficient of variation of glucose levels, as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Overnight period: Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Between night variability
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Total insulin dose overnight
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Day period: Proportion of time with glucose levels in target range (5.6-10.0mmol/l) as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 day
measure: Day period: Average glucose levels, as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 day
measure: Day period: Standard deviation and coefficient of variation of glucose levels, as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 day
measure: Day period: Area under the curve of sensor glucose levels below 3.5 mmol/l as recorded by CGM
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 day
measure: Between day variability
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 day
measure: Total insulin dose during the day
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days
measure: Safety: Number of subjects and number of occurences of severe hypoglycaemic events (capillary glucose <2.2mmol/l)
timeFrame: Phase 2-3 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
measure: Safety: Significant hyperglycaemic events (capillary glucose >20mmol/l) with or without ketonaemia (B-OHB >0.6mmol/l)
timeFrame: Phase 2 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
measure: Safety: Number of other (serious) adverse events (including adverse device effects) and device deficiencies
timeFrame: Phase 2 (Follow-up study) = Up to 15 days, Phase 4 = up to 4 weeks
measure: 2-hour postprandial incremental plasma glucose (Phase 4 only)
timeFrame: 120min after meal intake
measure: Peak glucose (Phase 4 only)
timeFrame: over 10 hours
measure: Mean insulin concentration (Phase 4 only)
timeFrame: over 10 hours
measure: Time to maximal insulin concentration (Phase 4 only)
timeFrame: over 10 hours
measure: Maximal insulin concentration (Phase 4 only)
timeFrame: over 10 hours
measure: Total and endogenous insulin exposure within 1 hour postprandial period (Phase 4 only)
timeFrame: over 10 hours
Locations:
city: Bern
country: Switzerland
facility: Inselspital, Bern University Hospital, University of Bern, Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
Study officials:
affiliation: University of Cambridge
name: Roman Hovorka, PhD, MSc, BSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bally L, Gubler P, Thabit H, Hartnell S, Ruan Y, Wilinska ME, Evans ML, Semmo M, Vogt B, Coll AP, Stettler C, Hovorka R. Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis. Kidney Int. 2019 Sep;96(3):593-596. doi: 10.1016/j.kint.2019.03.006. Epub 2019 Mar 20.
citation: Boughton CK, Bally L, Martignoni F, Hartnell S, Herzig D, Vogt A, Wertli MM, Wilinska ME, Evans ML, Coll AP, Stettler C, Hovorka R. Fully closed-loop insulin delivery in inpatients receiving nutritional support: a two-centre, open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2019 May;7(5):368-377. doi: 10.1016/S2213-8587(19)30061-0. Epub 2019 Mar 29.
citation: Bally L, Thabit H, Hartnell S, Andereggen E, Ruan Y, Wilinska ME, Evans ML, Wertli MM, Coll AP, Stettler C, Hovorka R. Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care. N Engl J Med. 2018 Aug 9;379(6):547-556. doi: 10.1056/NEJMoa1805233. Epub 2018 Jun 25.
citation: Thabit H, Hartnell S, Allen JM, Lake A, Wilinska ME, Ruan Y, Evans ML, Coll AP, Hovorka R. Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, parallel-group trial. Lancet Diabetes Endocrinol. 2017 Feb;5(2):117-124. doi: 10.1016/S2213-8587(16)30280-7. Epub 2016 Nov 9.