Clinical Assessment of a Closed-loop System With Glucagon, Exercise and Mixed Meals

The diabetes technology group at Imperial College have developed a bio-inspired artificial pancreas (BiAP) system which uses a control algorithm based on a mathematical model of beta-cell physiology. The algorithm is implemented on a miniature silicon microchip within a portable handheld device, which interfaces the components of the artificial pancreas.

Development of closed-loop insulin delivery devices to intensify control without hypoglycaemia has been extensively reviewed and have shown encouraging results . However, they have not yet proven to be robust when challenged with uncertainty and the external challenges (such as mixed meal contents, physical exercise, physiological stress and intercurrent illness) that people with Type 1 Diabetes Mellitus (T1DM) may be exposed to outside the clinical environment.

The principal research objective is to assess the safety and efficacy of a closed-loop system for T1DM compared to standard insulin pump therapy (open-loop). The primary outcome from the studies will be % time spent with a glucose concentration in the target range (3.9-10.0mmol/l). This outcome incorporates safety as it ensures subjects do not have low or high glucose excursions and is the principal measure of efficacy for closed-loop insulin delivery systems in the scientific literature. Other measured outcomes will be % time spent in euglycaemia (3.9-7.8mmol/l), % time spent in hypoglycaemia (\<3.9mmol/l), % time spent in hyperglycaemia (\>10mmol/l), mean venous blood and sensor glucose, glycaemic variability as measured by standard metrics (Standard Deviation, Continuous Overlapping Net Glycaemic Action, Lability Index, J-Index, Glycaemic Risk Assessment Diabetes Equation, Mean Of Daily Differences, Mean Amplitude of Glucose Excursion, Average Daily Risk Range, M-VALUE, Mean Average Glucose), glycaemic risk as measured by Low Blood Glucose Index (LBGI) and High Blood Glucose Index (HBGI), closed-loop error grid analysis, glucose area under the curve. All measures have been previously published and validated.

This clinical trial protocol assesses the artificial pancreas system in three separate sub-studies:

1. In a bi-hormonal (insulin and glucagon) configuration
2. During and after exercise with bi-hormonal closed loop, and standard insulin opened loop
3. During and after meals of mixed composition with bi-hormonal closed loop, and standard insulin opened loop

Methodology Randomised controlled cross-over open label study

Sub study 1 (n=10)

In sub-study 1 which includes the first bio-inspired artificial pancreas study using bi-hormonal (insulin and glucagon) control a fasting 6-hour bi-hormonal closed-loop study will be conducted to assess proof of concept and safety prior to the 25-hour randomised controlled crossover study

Each subject will then be randomised to attend either a closed-loop visit or an open-loop visit first. Once either visit is completed each subject will crossover and attend the remaining visit.

Sub-study 2 (n=20) The aim of sub-study 2 is to challenge the bi-hormonal pump during a moderate exercise. Subjects will be initially randomised to either the bi-hormonal or the standard opened loop and then cross over. Each study will last for 25 hours

• Exercise protocol: Subjects will be connected to the gas analyser and heart rate/ECG monitor as per COSMED manufacturer instructions.

The oxygen consumption (VO2)/Carbon dioxide production (VCO2) and heart rate/ECG trace will be displayed continuously in real time while the subject is exercising.

Warm-up: 3 minutes of cycling at low resistance (20-30 watts) while maintaining a speed of 60-80 revolutions per minute After the warm-up the subjects will undergo a 30 minutes moderate intensity exercise session on the bike aiming to maintain their VO2 between 10-20% above their 1st ventilatory anaerobic threshold. If their VO2 falls below or goes above this level then the resistance will be increased or decreased accordingly. The target VO2 and the starting resistance (watts) will be individually set based on their baseline exercise test outcome.

The estimated time needed to complete the exercise test is 35-40 minutes.

Real-time continuous glucose monitoring alarms will be set at 4mmol/L and 15mmol/L and will be audible by the subject and the research team.

The glucagon solution will be replaced with a freshly reconstituted glucagon solution every 8 hours throughout the closed-loop study If the venous blood glucose concentrations fall below 3.5mmol/L or if the subject experiences hypoglycaemia symptoms then hypoglycaemia will be confirmed by an additional venous blood plasma glucose sample and will be treated according to Imperial College Hospitals National Health Service Trust Guidelines.

After 25 hours of closed-loop, at 12:00 the next day, the subject's own insulin pump will be primed, reconnected and started as per the subject's usual insulin regime. Once running, the closed loop system will be disconnected. The subject can then eat and drink freely and may be discharged after 2 hours, or when glucose concentrations are stable.

The same protocol will be used when subjects cross over for the standard opened loop 25 hour study for the remaining visit.

Sub-study 3: Bi-hormonal closed-loop control during- and after mixed meals (n=20) A high fat/high carbohydrate content dinner (45g fat, 80g CHO) will be given at 19:00, a high glycaemic index breakfast (40g CHO) at 07:00 and a high protein/low carbohydrate lunch ( 30g protein,10g CHO) at 12:00.

Subjects will be free to gently mobilise around the clinical research unit, smoking will not be permitted. Subjects may drink unlimited water throughout the visit.

Real-time continuous glucose monitoring alarms will be set at 4mmol/L and 15mmol/L and will be audible by the subject and the research team.

The glucagon solution will be replaced with a freshly reconstituted glucagon solution every 8 hours throughout the closed-loop studies.

If the venous blood glucose concentrations fall below 3.5mmol/L or if the subject experiences hypoglycaemia symptoms then hypoglycaemia will be confirmed by an additional venous blood plasma glucose sample and will be treated according to Imperial College Hospitals National Health Service Trust Guidelines.

After 25 hours of closed-loop, at 18:00 the next day, the subject's own insulin pump will be primed, reconnected and started as per the subject's usual insulin regime. Once running, the closed-loop system will be disconnected. The subject can then eat and drink freely and may be discharged after 2 hours, or when glucose concentrations are stable.

The same protocol will be applied after cross over but with a standard opened loop insulin pump for the remaining visit.

Eligibility Criteria:
Inclusion Criteria:

* Adults over 18 years of age
* Type 1 diabetes confirmed on the basis of clinical features and a fasting c-peptide \<200 pmol/L
* Type 1 diabetes for greater than 1 year
* Continuous subcutaneous insulin infusion for greater than 6 months
* HbA1c \< 10% (86mmol/mol)

Exclusion Criteria:

* Recurrent severe hypoglycaemia and hypoglycaemia unawareness
* Pregnant or planning pregnancy
* Breastfeeding
* Enrolled in other clinical trials
* Have active malignancy or under investigation for malignancy
* Allergic to lactose
* Allergic to glucagon