Closing the Loop 24/7 in Adolescents With Type 1 Diabetes

Study Overview
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Brief Summary
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Type 1 diabetes (T1D) is one of the most common chronic childhood diseases requiring lifelong insulin therapy. Children and adolescents with T1D need regular insulin injections or the continuous insulin delivery using an insulin pump in order to keep blood glucose levels normal. We know that keeping blood sugars in the normal range will help prevent long-term diabetes-related complications involving the eyes, kidneys and heart. However, achieving treatment goals can be very difficult particularly due to the risk of low glucose levels (hypoglycaemia). One solution is to use a system where the amount of insulin injected closely matches the blood sugar levels on a continuous basis. This can be achieved by what is known as a closed-loop system where a small glucose sensor placed under the skin communicates with a computer containing an algorithm that drives a subcutaneous insulin pump. We have been testing such a system in Cambridge over the last five years in children and have found that this system is effective, and superior to usual insulin pump therapy, at maintaining tight glucose control. More recently the system has been tested overnight, in the home setting, for three weeks in adolescents during a pilot single-centre study. The next step is to evaluate use of the closed loop system day and night over a period of 7 days (phase 1) and 21 days (phase 2) in adolescents with type 1 diabetes. In the present study we are planning to study 24 (12 phase 1 ans 12 phase 2) young people aged 10-18 years on insulin pump therapy. This study will involve two 7 (phase 1) and 21 (phase 2) day home study periods, during which glucose levels will be controlled either by an automated closed-loop system or by subjects usual insulin pump therapy combined with continuous glucose monitoring alone in random order. Prior to the closed-loop study period, there will be a training period in the clinical research facility, which will allow participants to familiarise themselves with the closed-loop system before going home. We aim to to determine the effect of the closed-loop computer algorithm in keeping glucose levels between 3.9 and 10.0 mmol/L during the daytime and overnight.

Detailed Description
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The main objective of this study is to determine the efficacy, safety and utility of automated closed-loop glucose control in the home setting over a short term period, including the daytime and during the activities of normal daily living. This study builds on previous and on-going studies of closed-loop systems that have been performed in Cambridge in children and adolescents with type 1 diabetes in the clinical research facility and in the home setting. The data and experienced gained from this study will be utilised in planning future home studies. This is an open-label, single-centre, randomised, crossover study, involving two, 7 day (phase 1) and 21 day (phase 2) home study periods during which glucose levels will be controlled either by an automated closed-loop system or by subjects' usual insulin pump therapy combined with continuous glucose monitoring in random order. A total of up to 30 children and adolescents aged 10 to 18 years with T1D on insulin pump therapy will be recruited through diabetes clinics, to allow for 12 completed subjects available for assessment in each study phase. Subjects will receive appropriate training by the research team on the safe use of the closed-loop insulin delivery system. During the training visit in a clinical research centre, subjects will be encouraged to mimic their usual daily activities and will be allowed to walk inside hospital premises. Subjects will be advised to discontinue automated closed-loop insulin delivery and follow their usual insulin pump therapy for certain activities such as periods of strenuous exercise during the 7 day (phase 1) and 21 day (phase 2) home study phase. The primary outcome is time spent in target range between 3.9 and 10.0 mmol/L as recorded by CGM (conservatively adjusted for potential over-estimation). Secondary outcomes are the time spent with glucose levels above and below target, as recorded by CGM, and other CGM-based metrics. Safety evaluation comprises the tabulation of severe hypoglycaemic episodes.

Official Title
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An Open-label, Single-centre, Randomised, Two-period Crossover Study to Assess the Efficacy, Safety and Utility of Automated Closed-loop Glucose Control, Day and Night Over 7 Days (Phase 1) and 21 Days (Phase 2) in Comparison With Continuous Subcutaneous Insulin Infusion Combined With Continuous Glucose Monitoring in the Home Setting in Children and Adolescents T1D

Conditions
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Diabetes Mellitus, Diabetes Mellitus, Type 1, Glucose Metabolism Disorders, Endocrine System Diseases

Intervention / Treatment
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* Device: Closed-loop system
* Device: real-time CGM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is between 10 and 18 years of age (inclusive) The subject has type 1 diabetes, as defined by WHO for at least 1 year or is confirmed C-peptide negative The subject/carer will have been an insulin pump user for at least 3 months, with good knowledge of insulin self-adjustment as judged by the investigator The subject/carer is willing to perform regular finger-prick blood glucose monitoring, with at least 4 blood glucose measurements taken every day HbA1c between 7.0% and 11.0 % (53 to 97mmol/mol) based on analysis from central laboratory or equivalent The subject is literate in English The subject is willing to wear closed-loop system at home and at school / college / work The subject is willing to follow study specific instructions Exclusion Criteria: Non-type 1 diabetes mellitus including those secondary to chronic disease Any other physical or psychological disease or condition likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator. Current treatment with drugs known to have significant interference with glucose metabolism, such as systemic corticosteroids, as judged by the investigator Known or suspected allergy against insulin Subjects with clinically significant nephropathy, neuropathy or proliferative retinopathy as judged by the investigator Significantly reduced hypoglycaemia awareness as judged by the investigator Total daily insulin dose ≥ 2 IU/kg/day Total daily insulin dose <10 IU/day Reduced hypoglycaemia awareness Pregnancy, planned pregnancy or breast feeding Severe visual impairment Severe hearing impairment Subjects using implanted internal pacemaker Lack of reliable telephone facility for contact

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Closed-loop insulin delivery<br>Glucose level is controlled by the automated closed-loop glucose control system. After initial training with the closed-loop system devices, subjects will use the closed-loop system day and night at home for a total duration of 7 days (phase 1) and 21 days (phase 2). | Device: Closed-loop system<br>* The closed-loop system is purpose-built and comprises a hand-held computer containing a model predictive control (MPC) based glucose control algorithm and communicating with the CGM device and the insulin pump.<br>Device: real-time CGM<br>* Subject's glucose level is controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM)<br>|
| Active Comparator: real-time CGM alone<br>Glucose level will be controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM) during the day and night over 7 days (phase 1) and 21 days (phase 2). | Device: real-time CGM<br>* Subject's glucose level is controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of time spent in the target glucose range from 3.9 to 10.0 mmol/l based on CGM |  | 7 day (phase 1) and 21 day (phase 2) home study periods | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of time spent above and below the target glucose (3.9 to 10.0 mmol/l) based on CGM. |  | 7 day (phase 1) and 21 day (phase 2) home study periods | 
| The proportion of time with glucose levels < 3.5 mmol/l and <2.8 mmol/l based on CGM |  | 7 day (phase 1) and 21 day (phase 2) home study periods | 
| The proportion of time with glucose levels in significant hyperglycaemia, as based on CGM (glucose levels > 16.7 mmol/l) |  | 7 day (phase 1) and 21 day (phase 2) home study periods | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Closed-loop glucose control, Artificial Pancreas, Continuous subcutaneous insulin infusion, Continuous glucose monitoring