Closed-loop Control of Glucose Levels After Meal Intake in Adults 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 dosage based on the sensor's readings. A dual-hormone closed-loop system would regulate glucose levels through the infusion of two hormones: insulin and glucagon. The objective of this project is to assess whether a dual-hormone closed-loop strategy would alleviate the burden of carbohydrate counting from patients with type 1 diabetes (T1D) without a significant degradation in post-meal glucose control. Our primary hypothesis is that meal-announcement strategy (pre-meal CHO-independent bolus) is equivalent to meal-and-carbohydrate-announcement strategy (full CHO-matching bolus) during closed-loop regulation of glucose levels in adults with T1D. Our secondary hypothesis is that closed-loop strategy with meal-announcement strategy (pre-meal CHO-independent bolus) or meal-and-carbohydrate-announcement strategy (full CHO-matching bolus) is better than conventional pump treatment in regulation of glucose levels in adults with T1D.

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. Each patient will be admitted three times to a clinical research facility. In the meal-and-carbohydrate-announcement visit, patients will eat 3 meals accompanied with a matching insulin bolus (depending on the carbohydrate content of the meal) and glucose levels will be subsequently regulated using dual-hormone closed-loop system. In the meal-announcement visit, patients will eat the 3 same meals but will inject only a partial insulin bolus (not depending on carbohydrate content of the meal) and the remaining needed insulin will be delivered based on glucose sensor excursions as part of closed-loop operation. In the control visit, patients will use conventional pump therapy to regulate glucose levels.

Official Title
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An Open-label, Randomized, Three-way, Cross-over Study to Compare the Efficacy of Closed-loop Operation Combined With Meal-and-carbohydrate-announcement Closed-loop Operation Combined With Meal-announcement, and Conventional Pump Therapy in Regulating Glucose Levels in Adults With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Other: 14 hours intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years of old. Clinical diagnosis of type 1 diabetes for at least one year. The subject will have been on insulin pump therapy for at least 3 months. Last (less than 3 months) HbA1c ≤ 12%. Exclusion Criteria: Clinically significant microvascular complications: nephropathy (estimated glomerular filtration rate below 40 ml/min), neuropathy (especially diagnosed gastroparesis) or severe proliferative retinopathy as judged by the investigator. Recent (< 3 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery. Ongoing pregnancy. Severe hypoglycemic episode within two weeks of screening. Medication likely to affect with the interpretation of the results because of their well known impact on gastric emptying: Motilium®, Prandase®, Victoza®, Byetta® and Symlin®. Known or suspected allergy to the trial products, meal contents including nuts, peanuts, dairy products or eggs. Unusual nutritional habits (e.g. vegetarians) Other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator. Failure to comply with team's recommendations (e.g. not willing to eat snack, not willing to change pump parameters, etc). Unreliable carbohydrate counting or lack of insulin to carbohydrate ratios Problems with venous access

Ages Eligible for Study
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Minimum 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 |
| --- | --- |
| Active Comparator: CHO-dependant bolus<br>An insulin bolus dependant of carbohydrate content will be given after each meal. Each subject insulin-to-carbohydrate ratio (U per 10g CHO) will be used to calculate the insulin bolus to be given. The dual-hormone closed-loop strategy will give the remaining insulin needed based on the sensor readings. | Other: 14 hours intervention<br>* Subjects will be admitted at the IRCM at 6:30. Subjects will be asked to fast from midnight. At 8:00, a standardized (50g CHO for males; 30g CHO for females) meal will be served. At 12:00, a standardized (120g CHO for males; 90g CHO for females) meal will be served. At 17:00, a standardized (70g CHO for males; 50g CHO for females) meal will be served. Between meals, patients will be allowed to do sedentary activities (reading, watching television, and playing video games, etc).<br>|
| Active Comparator: CHO-independent bolus<br>An insulin bolus independent of carbohydrate content will be given after each meal. The dual-hormone closed-loop strategy will give the remaining insulin needed based on the sensor readings. | Other: 14 hours intervention<br>* Subjects will be admitted at the IRCM at 6:30. Subjects will be asked to fast from midnight. At 8:00, a standardized (50g CHO for males; 30g CHO for females) meal will be served. At 12:00, a standardized (120g CHO for males; 90g CHO for females) meal will be served. At 17:00, a standardized (70g CHO for males; 50g CHO for females) meal will be served. Between meals, patients will be allowed to do sedentary activities (reading, watching television, and playing video games, etc).<br>|
| Active Comparator: Conventional treatment<br>Patients will use conventional pump therapy to regulate glucose levels | Other: 14 hours intervention<br>* Subjects will be admitted at the IRCM at 6:30. Subjects will be asked to fast from midnight. At 8:00, a standardized (50g CHO for males; 30g CHO for females) meal will be served. At 12:00, a standardized (120g CHO for males; 90g CHO for females) meal will be served. At 17:00, a standardized (70g CHO for males; 50g CHO for females) meal will be served. Between meals, patients will be allowed to do sedentary activities (reading, watching television, and playing video games, etc).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The positive incremental area under the curve of postprandial glucose excursions | The positive incremental area under the curve (IAUC, as compared to pre-meal glucose value) of the 4-hr postprandial glucose excursions for the breakfast, lunch and dinner meals. | 4 hours after meal intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean plasma glucose |  | 8h00 to 21h00 | 
| Incremental two hours postprandial glucose |  | 2 hours after meal intake | 
| Incremental postprandial peak-glucose values |  | 8h00 to 21h00 | 
| Percentage of time of plasma glucose levels between 4.0 and 10.0 mmol/L |  | 8h00 to 21h00 | 
| Percentage of time of plasma glucose levels spent above 10.0 mmol/L |  | 8h00 to 21h00 | 
| Percentage of time of plasma glucose levels spent below 4.0 mmol/L |  | 8h00 to 21h00 | 
| Total insulin delivery |  | 8h00 to 21h00 | 
| Total glucagon delivery |  | 8h00 to 21h00 | 
| Standard deviation of glucose levels |  | 8h00 to 21h00 | 
| Percentage of time of plasma glucose concentrations below 3.5 mmol/L |  | 8h00 to 21h00 | 
| Percentage of time of plasma glucose concentrations above 14 mmol/L |  | 8h00 to 21h00 | 
| Mean plasma insulin concentration |  | 8h00 to 21h00 | 
| Mean plasma glucagon concentration |  | 8h00 to 21h00 | 
| Number of patients experiencing hypoglycemia requiring oral treatment |  | 8h00 to 21h00 | 
| Incremental area under the curve of the 4-hr postprandial glucose excursions but the reference glucose is set to 5.0 mmol/L if premeal glucose is less than 5.0 mmol/L. |  | 4 hours after meal intake | 

 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, Carbohydrate counting