Diabeloop for Highly Unstable Type 1 Diabetes

Study Overview
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Brief Summary
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Feasibility study, comparing experimental treatment (DBLHU closed-loop system) with reference treatment (Low Glucose Predictive Suspend system) in 7 patients going through a series of N-of-1 trials. Each N-of-1 trial consists in a prospectively planned, multiple crossover study in a single individual. Two blocks of two periods of four weeks each (closed loop or open loop) will be conducted. Within each block, the sequence closed loop-open loop or open loop-close loop is randomized. Outcomes will be analyzed on the third and fourth weeks of period. A remote monitoring system managed by specialized nurse on behalf of diabetologist, is provided in closed-loop session. An extension period of 48 weeks with the DBLHU System (closed-loop condition) will be performed at the end of the crossover study phase in real life conditions (without remote monitoring).

Official Title
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In Adults With Very Unstable Type 1 Diabetes, is the DBLHU Closed-Loop Insulin Delivery System Able to Improve Blood Glycemic Control Compared to Low-Glucose-Predictive-Suspend System: Two-center, Randomized, Open-label Study

Conditions
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Diabetes Mellitus, Type 1, Diabetes Mellitus, Brittle, Closed-Loop

Intervention / Treatment
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* Device: Low Glucose Predictive Suspend system
* Device: DBLHU System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject (aged 22 or more) with Type 1 diabetes for at least 5 years and confirmed C peptide negative Treated with continuous subcutaneous insulin infusion (CSII) for ≥ 6 months, Trained to carbohydrate counting/flexible insulin therapy, Subject that had experienced, despite optimal diabetes management and prior to any equipment with Smartguard technology, glucose instability as defined by at least 2 of the following criteria which would have led to eligibility for pancreatic islet transplantation: occurrence of at least 1 severe hypoglycemic episode during the past 12 months (need for third party), occurrence of ketoacidosis (hospitalization in ICU) without explanation Impaired awareness of hypoglycemia (Clark Score ≥ 4; Gold Score > 4) glucose levels: standard deviation > 50% of the arithmetic mean value on glucose meter or > 40 mg/dl on CGM on a 14-day recording glucose levels: MAGE (mean amplitude of glucose excursions) index > 60 mg/dl glucose levels: coefficient of variation (CV) > 36% with persisting extreme glucose variability despite optimal medical care with contra-indication or no agreement to undertake pancreatic islet transplantation or pancreas transplantation. Subject willing to wear the DBLHU system continuously throughout the study Exclusion Criteria: patient with type 2 diabetes age < 22 years old patient without any social or familial support able to intervene in case of severe hypoglycemic event any permanent and severe condition able to interact with the normal course of the study patient with insulin-resistance defined by insulin requirements > 1.5U/kg/d patient with a daily dose of insulin required greater than 90 units patient receiving a total daily dose of insulin less than 8 U use of any insulin that is not 100 U/mL fast-acting insulin analog patient suffering from a serious illness or a treatment that might significantly impair diabetes physiology, i.e. glucose-insulin interactions, that might interfere with the medical device (for example irregular treatment of steroids) patient having severe problems of uncorrected hearing and/or visual acuity patient who is unable to understand and perform all the instructions provided by Diabeloop SA patient not willing to perform ≥4 finger stick blood glucose measurements daily patients that have frequent exposure to magnetic resonance imaging (MRI), computed tomography (CT) scan, or high-frequency electrical heat (diathermy) treatment. patient who has had a pancreatectomy or who has pancreatic malfunctions patient having severely altered renal function (Creatinine clearance < 30ml/min) patient on dialysis pregnancy or breast-feeding patient, or project of pregnancy during the next 6 months lack of effective contraception in women of childbearing potential all conditions excluding participation to clinical research as defined in France

Ages Eligible for Study
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Minimum Age: 22 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: Device Feasibility
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: N-of-1 trials consists in a prospectively planned, multiple crossover study in a single individual.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reference treatment (Open-Loop)<br>Sensor-augmented pump therapy (SAP) namely the Low Glucose Predictive Suspend system or LGPS and a blinded glucose sensor (Dexcom G6) followed by a 48-week extension period in closed-loop condition | Device: Low Glucose Predictive Suspend system<br>* consists of sensor-augmented pump therapy (SAP) / Low Glucose Predictive Suspend system (with predictive low glucose management technology)<br>* Other names: Open-loop condition;Device: DBLHU System<br>* DBLHU system embeds a regulation algorithm to automatically regulate the patient's glycaemia. It takes as input glycaemia value received every 5 minutes from the CGM and patient inputs related to meals and physical activities and it calculates the amount of insulin to be delivered. It sends this information to the pump that automatically delivers this quantity.<br>* Other names: Closed-loop condition;|
| Experimental: DBLHU system (Closed-Loop)<br>DBLHU software (a Model Predictive Control [MPC]-based glucose control algorithm) running on handset associated with the six-generation glucose sensor (Dexcom G6) and Kaleido insulin pump followed by a 48-week extension period in closed-loop condition | Device: DBLHU System<br>* DBLHU system embeds a regulation algorithm to automatically regulate the patient's glycaemia. It takes as input glycaemia value received every 5 minutes from the CGM and patient inputs related to meals and physical activities and it calculates the amount of insulin to be delivered. It sends this information to the pump that automatically delivers this quantity.<br>* Other names: Closed-loop condition;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of CGM time in glucose range 70-180 mg/dl, during 24 hours periods for the third and fourth week for each treatment period | Measured by continuous glucose monitoring | 14 days for each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution over time of the DBLHU system's performance on a day-to-day and determination of the optimization delay of glycemic control | Measured by continuous glucose monitoring | Over twenty-four hour periods on the four weeks of each treatment period and of the 24-week and 48-week extented CL period. | 
| Percent of CGM time in glucose range 70-180 mg/dl during nighttime. | Measured by continuous glucose monitoring | Overnight (defined as 00:00 to 06:00) periods on the third and fourth week of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Percent of CGM time in glucose range 70-180 mg/dl during daytime. | Measured by continuous glucose monitoring | Over daytime (defined as 06:00 to 00:00) periods on the third and fourth week of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Percent of CGM time with glucose < 70mg/dl, < 60mg/dl, < 54mg/dl and < 50mg/dl | Measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Percent of CGM time with glucose > 180mg/dl, > 250mg/dl, > 300mg/dl and > 360mg/dl | Measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Average glycemia level | Measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Estimated HbA1c (eHbA1c) levels / glucose management indicator (GMI) | Measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| HbA1c levels | Measured by blood sampling | HbA1c value at the week 24 and week 48 of extented CL period. | 
| Glucose coefficient of variation (CV) and Standard deviation (SD) | Measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Rate of CGM excursions below 54 mg/dl (3.0 mM) for at least 15 min | Mean time spent in hypoglycaemia, defined as sensor glucose values of 54 mg/dL (3∙0 mmol/L) or lower for more than 15 min consecutively | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during the last 4 weeks of the 24-week and 48-week extented CL period. | 
| Comparison of MAGE index and Low Blood Glucose Index (LBGI) | Mean amplitude of glucose excursions and Low Glucose index as measured by continuous glucose monitoring | Over twenty-four hour periods on the third and fourth weeks of each treatment period and during 24-week extension period | 
| Number of acute metabolic events (severe hypoglycemia, severe Diabetic Ketoacidosis [DKA]) | Measured by continuous glucose monitoring. Number of severe hypoglycemia is defined as any event requiring third party assistance. DKA events. Subjects will be asked to measure blood ketone levels on if their interstitial glucose is above 300 mg/l beyond the usual timeframe following a meal, as part of the safety evaluation for hyperglycemia. | During 4 weeks of each treatment period and during 24-week and 48-week extension period | 
| Number of severe hypoglycemia with loss of consciousness | Number of severe hypoglycemia with loss of consciousness | During 4 weeks of each treatment period and during 24-week and 48-week extension period | 
| Number of hospitalizations for severe hypoglycemia or ketoacidosis | Number of hospitalizations | During 4 weeks of each treatment period and during 24-week and 48-week extension period | 
| For the use and the acceptance, a satisfaction survey will be done on the daily management of diabetes, the modification of daily life with the system dan the fear of hypoglycemia | DTSQ satisfaction questionnaire, with scale from 6 to 0 where 0 is the worth and 6 the best outcome. | after baseline period (2-week); after crossover period; after 24-week and after 48-week extension period | 
| Percentage of CGM time in glucose range 70-180 mg/dl, during 24 hours periods | Measured by continuous glucose monitoring | 24-week and 48-week extension period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artificial pancreas, Very Unstable Type 1 diabetes