Closed-loop Control of Overnight Glucose Levels in Adults and Adolescents With Type 1 Diabetes

Study Overview
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Brief Summary
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Closed-loop strategy is composed of three components: glucose sensor to read glucose levels, insulin pump to infuse insulin and a dosing mathematical algorithm to decide on the required insulin dosages based on the sensor's readings. A dual-hormone closed-loop system would regulate glucose levels through the infusion of two hormone: insulin and glucagon. The main objective of this project is to compare the efficacy of single-hormone closed-loop strategy, dual-hormone closed-loop strategy and pump therapy to regulate overnight glucose levels in a out-patient study in adults and adolescents with type 1 diabetes. The investigators hypothesized that dual-hormone closed-loop strategy is more effective in regulating overnight glucose levels in adults and adolescents with type 1 diabetes compared to single-hormone closed-loop strategy, which in turn is more effective than the conventional pump therapy.

Detailed Description
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Closed-loop strategy is composed of three components: glucose sensor to read glucose levels, insulin pump to infuse insulin and a dosing mathematical algorithm to decide on the required insulin dosages based on the sensor's readings. A dual-hormone closed-loop system would regulate glucose levels through the infusion of two hormone: insulin and glucagon. We aim to conduct a multicenter study to compare the efficacy of conventional pump therapy, single-hormone closed-loop strategy and dual-hormone closed-loop strategy to regulate overnight glucose levels, at home, in adolescents and adults with type 1 diabetes. Each intervention will be tested on two nights: 1) After a carbohydrate-rich dinner meal (to exaggerate hyperglycemic risk and; 2) After an evening exercise (to exaggerate hypoglycemic risk).

Official Title
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An Open-label, Randomized, Three-way, Multicenter Study to Compare the Efficacy of Single-hormone Closed-loop Strategy, Dual-hormone Closed-loop Strategy and Conventional Insulin Pump Therapy in Regulating Overnight Glucose Levels at Home in Adolescents and Adults With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Other: Carbohydrate-rich meal
* Other: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged ≥ 12 years of old. Body mass index < 35 Clinical diagnosis of type 1 diabetes for at least one year. The subject will have been on insulin pump therapy for at least 4 months. HbA1c < 12%. At least two visits with an endocrinology team in the past 1 year. Exclusion Criteria: Clinically significant nephropathy, neuropathy (peripheral or autonomic e.g. significant gastroparesis) or retinopathy as judged by the investigator. Recent (< 6 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery. A recent injury to body or limb, muscular disorder, use of any medication or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the exercise protocol. Ongoing pregnancy. Severe hypoglycemic episode within two weeks of screening. Current use of glucocorticoid medication (except low stable dose and inhaled therapy). Known or suspected allergy to the insulin aspart, glucagon, Medtronic sensors, or Medtronic infusion sets.. Other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator. Anticipating a significant change in treatment regimen between admissions (such as a major change in an exercise routine, significant change in dietary routine or in insulin therapy. Failure to comply with team's recommendations.

Ages Eligible for Study
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Minimum Age: 12 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 |
| --- | --- |
| Active Comparator: Conventional insulin pump therapry<br>Subjects will use conventional pump therapy to regulate their glucose levels. | Other: Carbohydrate-rich meal<br>* At 19:30, patients will eat a standardized large meal (110g carbohydrate for males; 90g carbohydrate for females). Conventional insulin pump therapy or closed-loop system will be use to control glucose levels from 21:00 until 7:00 next morning.<br>Other: Exercise<br>* Study participants will go to a training facility around 18:00 to perform a 60min workout at 60% heart rate reserve. The workout will be on a treadmill and/or a stationary bicycle. Conventional insulin pump therapy or closed-loop system will be use to regulate glucose levels from 21:00 until 7:00 next morning.<br>|
| Active Comparator: Single-hormone closed-loop system<br>Variable subcutaneous insulin infusion rate will be used to regulate glucose levels. Insulin Aspart (Novorapid) will be infused using a subcutaneous infusion pump. The glucose level as measured by the real time sensor will be entered manually into the computer every 10 minutes. The pump's infusion rate will then be changed manually based on the computer-generated recommendations of infusion rates. | Other: Carbohydrate-rich meal<br>* At 19:30, patients will eat a standardized large meal (110g carbohydrate for males; 90g carbohydrate for females). Conventional insulin pump therapy or closed-loop system will be use to control glucose levels from 21:00 until 7:00 next morning.<br>Other: Exercise<br>* Study participants will go to a training facility around 18:00 to perform a 60min workout at 60% heart rate reserve. The workout will be on a treadmill and/or a stationary bicycle. Conventional insulin pump therapy or closed-loop system will be use to regulate glucose levels from 21:00 until 7:00 next morning.<br>|
| Active Comparator: Dual-hormone closed-loop system<br>Insulin Aspart (Novorapid) and glucagon (Paladin) will be infused using two separate subcutaneous infusion pumps. The glucose levels as measured by the real time sensor will be entered manually into the computer every 10 minutes. The pumps' infusion rate will then be changed manually based on the computer generated-recommendation delivery levels. | Other: Carbohydrate-rich meal<br>* At 19:30, patients will eat a standardized large meal (110g carbohydrate for males; 90g carbohydrate for females). Conventional insulin pump therapy or closed-loop system will be use to control glucose levels from 21:00 until 7:00 next morning.<br>Other: Exercise<br>* Study participants will go to a training facility around 18:00 to perform a 60min workout at 60% heart rate reserve. The workout will be on a treadmill and/or a stationary bicycle. Conventional insulin pump therapy or closed-loop system will be use to regulate glucose levels from 21:00 until 7:00 next morning.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time in target range | Percentage of time for which glucose levels (as measured by the glucose sensor) are in target range. Target range is defined to be between 4.0 to 8.0 mmol/L | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time in target range for each night separately | Percentage of time for which glucose levels are in target range for each night separately. Target range is defined to be between 4.0 and 8.0 mmol/L. | 8 hours | 
| Percentage of time in target range for the pooled data | Percentage of time for which glucose levels are in target range for the pooled data. Target range is defined to be between 4.0 to 8.0 mmol/L. | 8 hours | 
| Percentage of time spent below 4.0 mmol/L | Percentage of time for which glucose levels are below 4.0 mmol/L. | 8 hours | 
| Percentage of time spent below 3.3 mmol/L | Percentage of time for which glucose levels are spent below 3.3 mmol/L. | 8 hours | 
| Area under the curve for glucose levels below 4.0 mmol/L |  | 8 hours | 
| Area under the curve for glucose levels below 3.3 mmol/L |  | 8 hours | 
| Percentage of time spent above 8.0 mmol/L | Percentage of time for which glucose levels are above 8.0 mmol/L | 8 hours | 
| Percentage of time spent above 10.0 mmol/L | Percentage of time for which glucose levels are above 10.0 mmol/L. | 8 hours | 
| Area under the curve for glucose levels spent above 8.0 mmol/L |  | 8 hours | 
| Area under the curve for glucose levels spent above 10.0 mmol/L |  | 8 hours | 
| Mean glucose levels |  | 8 hours | 
| Standard deviation of glucose levels | Standard deviation of glucose levels as a measure of glucose variability. | 8 hours | 
| Total insulin delivery |  | 8 hours | 
| Number of subjects experiencing at least one hypoglycemic event requiring treatment |  | 8 hours | 
| Number of hypoglycemic events requiring treatment |  | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Hypoglycemia, Insulin, Glucagon, Closed-loop system, Artificial pancreas