Looping Whilst Restricting Carbohydrates

Study Overview
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Brief Summary
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To investigate the efficacy, safety and utility of hybrid closed-loop glucose control during a low carbohydrate vs. iso-energetic balanced diet in individuals with type 1 diabetes.

Detailed Description
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Closed-loop systems combining an insulin pump, a glucose sensor and a dosing algorithm that adjusts insulin delivery in a glucose-responsive manner achieve significantly better glucose control than conventional therapy in type 1 diabetes. Achieving satisfactory postprandial glucose control, however, continues to be challenging. The main limitation is the delayed pharmacokinetics and -dynamics of subcutaneously administered insulin with peak actions between 1 and 2 hours. Conversely, glucose levels typically rise within 10minutes following carbohydrate intake. This mismatch largely explains the inability of current closed-loop systems to control postprandial glucose excursions and the increased risk of late postprandial hypoglycaemia in response to both user-derived meal bolus administration and reactive algorithm-driven insulin infusion. Restricting carbohydrate may therefore significantly improve post-prandial glucose control whilst reducing hypoglycaemia. The efficacy of hybrid closed-loop operation in individuals with type 1 diabetes adhering to a low carbohydrate compared to a iso-caloric balanced diet has not been investigated to date.

Official Title
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Looping Whilst Restricting Carbohydrates (LINEAR) - a Randomised Two-Period Crossover Trial

Conditions
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Diabetes, Type 1 Diabetes

Intervention / Treatment
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* Other: Low carbohydrate diet
* Other: balanced diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female and male subjects aged 18 years or older Diabetes mellitus Type 1 as definded by WHO for at least 2 years or C-peptide negative (<100 pmol/L with concomitant blood glucose > 4 mmol/L) hybrid-closed-loop Insulin therapy (Minimed 670G) for at least 2 months HbA1c <= 9 % The subject is willing and capable of adhering to the diet plan. Exclusion Criteria: Physical or psychological condition likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator. Excess alcohol consumption (> 3 units/day for men, > 2 units/day for women) Pregnancy, planned pregnancy or breast feeding Current participation in another clinical trial Total daily insulin dose >2 IU/kg/day Nephrolithiasis Hereditary dyslipidemia Liver steatosis

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 |
| --- | --- |
| Experimental: Study intervention<br> | Other: Low carbohydrate diet<br>* The study intervention will be an eucaloric low carbohydrate diet (15-20 % of carbohydrates) for 2 weeks.<br>|
| Active Comparator: Control intervention<br> | Other: balanced diet<br>* The control intervention will be a energy-matched balanced diet (50 % of carbohydrates) for 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time in target glucose range (3.9 - 10.0 mmol/L) | The percentage of time in target glucose range will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time above target (>10 mmol/L) | The percentage of time below target (>10 mmol/L) will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Percentage of time below target (<3.9 mmol/L) | The percentage of time below target (<3.9 mmol/L) will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Percentage of time in hypoglycemia (<3.0 mmol/L) | The percentage of time in hypoglycemia (<3.0 mmol/L) will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Hypoglycemia burden quantified as the area under the curve (AUC) with glucose < 3 mmol/L | Hypoglycemia burden will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Percentage of time in hyperglycemia (>16.7 mmol/L) | The percentage of time in hyperglycemia (>16.7 mmol/L) will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Mean glucose levels (mmol/l) | Mean sensor glucose levels will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Total daily insulin dose (U) | Total daily insulin dose will be recorded by the insulin pump | 2 weeks | 
| Daily manual bolus Insulin dose (U) | Daily manual bolus insulin dose will be recorded by the insulin pump | 2 weeks | 
| 2 hour postprandial glucose increment (mmol/) | 2 hour postprandial glucose increment will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Within-day standard deviation of glucose (mmol/l) | Within-day standard deviation of glucose will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Within day coefficient of variation of glucose (%) | Within day coefficient of variation of glucose will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Between days coefficient of variation of glucose (%) | Between days coefficient of variation of glucose will be assessed using continuous glucose monitoring (CGM). | 2 weeks | 
| Night-time percentage of time in target glucose range (3.9 - 10.0 mmol/L) | Percentage of time in target glucose range will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Night-time percentage of time above target (> 10.0 mmol/L) | Percentage of time above target will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Night-time percentage of time below target (< 3.9 mmol/L) | Percentage of time below target will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Night-time percentage of time in hypoglycemia (< 3.0 mmol/L) | Percentage of time in hypoglycemia will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Night-time percentage of time in hyperglycemia (> 16.7 mmol/L) | Percentage of time in hyperglycemia will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Night-time mean glucose levels | Mean sensor glucose levels will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Within night-time standard deviation of glucose (mmol/l)compared to within daytime period (06: - 24:00) standard deviation of glucose (mmol/l) | Standard deviation of glucose will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Within nighttime coefficient of variation of glucose(%) | Coefficient of variation of glucose (%) will be assessed using continuous glucose monitoring (CGM). | Between 00:00-06:00 over 2 weeks | 
| Change from baseline in lipid profile | Plasma Lipid profile (total Cholesterol, LDL-Cholesterol, HDL-Cholesterol, Triglycerides) | 2 weeks | 
| Total daily calorie intake (kcal/day) | Total daily calorie intake will be assessed based on photo-documentation of dietary intake | 2 weeks | 
| Mean beta-hydroxy butyrate level | based on download of blood Ketone meter | 2 weeks | 
| Change from baseline in fasting plasma metabolome | Fasting serum sampling | 2 weeks | 
| Incidence of (serious) adverse events | Incidence of severe hypoglycaemia, signficant hyperglycaemia with ketonemia, other SAEs, adverse events, adverse defice effects and device deficiencies | 12 weeks | 
| Percentage of time when pump was in Auto-mode | Based on pump data download | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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artificial pancreas, hybrid closed-loop, low carbohydrate diet, glucose control