Closed Loop Glucose Control in Intensive Care Unit (CLASSIC)

An Open-label, Single-centre, Randomised Controlled Trial to Assess the Safety and Efficacy of Automated Closed-loop Blood Glucose Control in Comparison With Standard Care in Adults in Intensive Care Unit

The purpose of this study is to assess the efficacy, safety and feasibility of a computer-based control algorithm to control glucose levels in adults in intensive care unit, in comparison to standard care.

Study Overview

• Status: Completed
• Conditions: Stress Hyperglycaemia
• Intervention / Treatment: Other: Closed-loop insulin delivery; Other: Standard IV insulin infusion sliding scale

Detailed Description

This will be a single centre, open-label, randomised, parallel design, feasibility study conducted at Neurosciences Critical Care Unit (NCCU), Addenbrooke's hospital, Cambridge, UK. Study will aim for 24 adult subjects (12 participants in each arm of the trial) and study will last for up to 49 hours in each subject. Subjects will have a commercially available Conformité Européenne(CE) marked subcutaneous glucose sensor inserted at the start of the study. Glucose data from the sensor will be transmitted to a small bedside tablet computer, containing the algorithm which will determine insulin infusion rates aimed at maintaining glucose level between 6.0 - 8.0 mmol/L. The advice from the algorithm will be sent to the infusion pump via USB cable and insulin will be delivered intravenously. The system will also deliver intravenous glucose via a second infusion pump at times of low glucose levels. Samples for reference glucose values will be obtained either from an arterial line or central venous cannula and will be analysed using standard blood gas analyser in real time. Subjects randomised to standard care will receive intravenous insulin based on current treatment guidelines at the Neurosciences critical care unit (NCCU), Addenbrooke's Hospital, Cambridge, UK.

The primary outcome is time spent in target glucose range between 6.0 to 8.0 mmol/L as recorded by reference glucose. Secondary outcomes are the time spent with glucose levels above and below target, as recorded by reference glucose, and sensor accuracy. Safety includes evaluation of significant hypoglycaemia and hyperglycaemia and other adverse events.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital

Participation Criteria

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:

• Aged 18 years and older
• Admitted to Neurosciences critical care unit; (all patients are eligible regardless of admitting diagnosis except where specified under exclusion criteria)
• Stay in intensive care unit expected to be at least 48 hours
• At least one of the following conditions applies:
• Not on insulin infusion and single confirmed reference blood glucose level > 10.0 mmol/l
• Already on insulin infusion including those subjects with pre-existing diabetes.

Exclusion Criteria:

• Patients with diabetic ketoacidosis or hyperosmolar hyperglycaemic non-ketotic coma (HONK)
• Patients who are receiving therapeutic hypothermia
• Known or suspected allergy to insulin
• Any disease or condition which the investigator or treating physician feels would interfere with the trial or the safety of the patient (i.e. liver failure, other fatal organ failures)
• Patients with significant abnormalities of blood clotting.
• Moribund patients likely to die within 48 hours
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Closed-loop (Model Predictive Control Algorithm)	Other: Closed-loop insulin delivery; Intravenous infusion delivery of Actrapid insulin and dextrose, dose calculated by Model Predictive Control (MPC) algorithm, based on continuous glucose sensor readings.
Active Comparator: Open loop (Standard treatment)	Other: Standard IV insulin infusion sliding scale; Standard intravenous insulin infusion sliding scale as per intensive care unit protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of glucose values in target range (6.0 - 8.0 mmol/l) as recorded by reference glucose measurements.	Definition of Reference glucose = Blood Glucose level measured by arterial blood gas analyzer. During the study subjects will have the reference glucose measured every 1 hour and this is used for the calculation percentage glucose values.	Up to 49 hours in each subject.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of glucose values in range (4.0 - 10.0 mmol/l) as recorded by reference glucose measurements.	Definition of Reference glucose = Blood Glucose level measured by arterial blood gas analyzer. During the study subjects will have the reference glucose measured every 1 hour and this is used for the calculation percentage glucose values.	Up to 49 hours in each subject
Percentage of glucose values <4.0 mmol/l and >8.0 mmol/l as recorded by reference glucose measurements.	Definition of Reference glucose = Blood Glucose level measured by arterial blood gas analyzer. During the study subjects will have the reference glucose measured every 1 hour and this is used for the calculation percentage glucose values.	Up to 49 hours in each subject.
Percentage of glucose values > 10.0 mmol/l as recorded by reference glucose measurements.	Definition of Reference glucose = Blood Glucose level measured by arterial blood gas analyzer. During the study subjects will have the reference glucose measured every 1 hour and this is used for the calculation percentage glucose values.	Up to 49 hours in each subject,
Mean and standard deviation of reference glucose measured using arterial blood gas analyzer	Definition of Reference glucose = Blood Glucose level measured by arterial blood gas analyzer. This is reported in mmol/L During the study subjects will have the reference glucose measured every 1 hour and this is used for the calculation of mean (mmol/L) and standard deviation which will reflect the efficasy of closed loop insulin delivery.	Up to 49 hours in each subject.
Mean and median absolute and relative difference between matched pairs of subcutaneous glucose sensor and reference plasma glucose.	For a given subcutaneous glucose sensor value, difference between the sensor and the reference glucose will be calculated. Example - Reference glucose 10 mmol/L and sensor glucose 12 mmol/L, therefore absolute difference will be 2 mmol/L. Mean and median of these deviations will be reported in mmol/L. The term relative implies that data has been converted to a percentage deviation from reference glucose.	Up to 49 hours in each subject.
Time to reach target glucose		Up to 49 hours in each subject.
Insulin infusion rates		Up to 49 hours in each subject.
Frequency and magnitude of significant hypoglycaemic (< 3.0 mmol/L), severe hypoglycaemic (<2.0 mmol/L) and significant hyperglycaemic (> 15mmol/l) episodes.		Up to 49 hours in each subject.

Collaborators and Investigators

• Sponsor: University of Cambridge
• Collaborators: Cambridge University Hospitals NHS Foundation Trust; European Commission
• Investigators: Principal Investigator: Roman Hovorka, BSc MSc PhD, University of Cambridge; Principal Investigator: Rowan Burnstein, MBBS FRCA PhD, Addenbrooke's Hospital, Cambridge, United Kingdom

Publications and helpful links

General Publications

• Leelarathna L, English SW, Thabit H, Caldwell K, Allen JM, Kumareswaran K, Wilinska ME, Nodale M, Mangat J, Evans ML, Burnstein R, Hovorka R. Feasibility of fully automated closed-loop glucose control using continuous subcutaneous glucose measurements in critical illness: a randomized controlled trial. Crit Care. 2013 Jul 24;17(4):R159. doi: 10.1186/cc12838.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: September 22, 2011
• First Submitted That Met QC Criteria: September 26, 2011
• First Posted (Estimate): September 27, 2011

Study Record Updates

• Last Update Posted (Estimate): January 3, 2013
• Last Update Submitted That Met QC Criteria: December 31, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Stress hyperglycaemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: CLASSIC 01