SAFE-AP: Automatic Control of Blood Glucose Under Announced and Unannounced Exercise

Study Overview
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Brief Summary
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Achieving near-normoglycemia has been established as the main objective for most patients with diabetes. Despite growing evidence about the health benefits of regular exercise in diabetes, exercise-associated glycemic imbalance remains a challenge in subjects with type 1 diabetes (T1D) due to a higher risk of hypoglycemia. Automatic glucose control, the so-called artificial pancreas (AP) or closed-loop system, may represent the ideal solution for reaching the therapeutic goals in diabetic patients. Intuitively, closed-loop insulin delivery may be superior to open-loop insulin delivery due to a better compensation of the variability of subcutaneous insulin absorption and the intra-subject insulin sensitivity. However, several challenges exist to effectively realize an optimal closed-loop control of blood glucose during exercise. Indeed, the physical exercise induces one of the major glucose perturbations that need to be controlled by an artificial pancreas and is currently one of the main challenges found in clinical validations of the few existing prototypes of an artificial pancreas. In particular, experiments carried out with the currently used algorithms for glucose control (the so called PID (proportional-integrative-derivative) and MPC) showed that closed-loop insulin delivery is deteriorated by exercise, increasing the risk of hypoglycemia even with pre-exercise carbohydrate ingestion when non-announcement strategies are used. In this project, a rigorous clinical testing of a novel closed-loop controller ('artificial pancreas') will be carried out in T1D patients treated with continuous subcutaneous insulin infusion (CSII). The innovative element of the controller is a safety auxiliary feedback based on sliding mode reference conditioning (SMRC), which has been demonstrated to limit over-insulinization and the resulting hypoglycemia, reducing glycaemic variability. Announced and unannounced exercise will be performed in T1D subjects treated with CSII, comparing the number of hypoglycemic episodes with a controller-driven insulin delivery (closed-loop study) based on continuous subcutaneous glucose monitoring (CGM). If any glucose value <70 mg/dL 15 gr of glucose will be provided. Moreover 15gr of glucose will be provided in AP studies when AP system recommends it. The hypothesis is that closed loop control will provide better glycemic control, with less hypoglycemia episodes.

Official Title
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SAFE-AP: Automatic Control of Blood Glucose Under Announced and Unannounced Exercise

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Device: Closed-loop controller with exercise mitigation module
* Device: Closed-loop controller without exercise mitigation module
* Device: Open-loop insulin infusion system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18-65 years. Under CSII treatment for at least six months before visit 1. Body mass index between 18 and 30 kg/m2. HbA1c 6.0-8.5% at visit 1. Physical examination, laboratory data and EKG without alterations. Abnormalities considered clinically irrelevant by the investigator will not be exclusion criteria. Postmenopausal women or women of childbearing age using contraceptives of proven effectiveness and with negative urine pregnancy test at screening visit. Exclusion Criteria: Pregnancy and breastfeeding. Hypoglycemia unawareness (Clarke Test >3). Progressive fatal disease. History of drug or alcohol abuse. History HIV positive, active hepatitis B or hepatitis C. Impaired liver function, as shown in, but not limited to, SGPT (serum gutamate pyruvate transaminase) or SGOT (serum glutamate oxaloacetate transaminase) more than twice the upper limit of normal at Visit 1. Clinically relevant microvascular complications (macroalbuminuria, pre-proliferative and proliferative retinopathy), cardiovascular, hepatic, neurological, endocrine or other systematic, apart from T1D, which may hamper the implementation of the clinical study protocol or interpretation of results study. Scheduled surgery during the study period. Mental conditions that prevent the subject to understand the nature, purpose and possible consequences of the study. Subjects those are unlikely to meet the clinical study protocol, eg uncooperative attitude, inability to return for follow-up visits, or poor probability of completing the study. Using an experimental drug or device during the past 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Longitudinal, prospective, interventional study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Closed-loop controller with exercise mitigation module<br>Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with mitigation module. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP with mitigation module) based on blood glucose estimations from CGM. | Device: Closed-loop controller with exercise mitigation module<br>* Each subject will undergo three exercise tests, each one at 1-2 week intervals, thus completing the 3 experiments in about 6 weeks. The day of the experiment, the participant will do 3 sets of 15 minutes of cycloergometer at 70% of VO2max with 5 minutes of rest between them. On the first arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with a mitigation mode, based on subcutaneous continuous glucose monitoring (First arm, Closed-loop study with mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Closed-loop controller without exercise mitigation module<br>* On the second arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration without a mitigation mode, based on subcutaneous continuous glucose monitoring (Second arm, Closed-loop study without mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Open-loop insulin infusion system<br>* Standard subcutaneous insulin infusion based on the individual insulin sensibility. Commercial insulin infusion systems and continuous subcutaneous glucose monitoring devices will be used.<br>|
| Experimental: Closed-loop controller without exercise mitigation module<br>Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFEAP without mitigation module) based on blood glucose estimations from CGM. | Device: Closed-loop controller with exercise mitigation module<br>* Each subject will undergo three exercise tests, each one at 1-2 week intervals, thus completing the 3 experiments in about 6 weeks. The day of the experiment, the participant will do 3 sets of 15 minutes of cycloergometer at 70% of VO2max with 5 minutes of rest between them. On the first arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with a mitigation mode, based on subcutaneous continuous glucose monitoring (First arm, Closed-loop study with mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Closed-loop controller without exercise mitigation module<br>* On the second arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration without a mitigation mode, based on subcutaneous continuous glucose monitoring (Second arm, Closed-loop study without mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Open-loop insulin infusion system<br>* Standard subcutaneous insulin infusion based on the individual insulin sensibility. Commercial insulin infusion systems and continuous subcutaneous glucose monitoring devices will be used.<br>|
| Active Comparator: Open-loop insulin infusion system<br>Standard Open-loop intensive insulin treatment with continuous subcutaneous insulin infusion (CSII). Commercially available insulin infusion systems will be used. | Device: Closed-loop controller with exercise mitigation module<br>* Each subject will undergo three exercise tests, each one at 1-2 week intervals, thus completing the 3 experiments in about 6 weeks. The day of the experiment, the participant will do 3 sets of 15 minutes of cycloergometer at 70% of VO2max with 5 minutes of rest between them. On the first arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration with a mitigation mode, based on subcutaneous continuous glucose monitoring (First arm, Closed-loop study with mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Closed-loop controller without exercise mitigation module<br>* On the second arm, participants will receive Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration without a mitigation mode, based on subcutaneous continuous glucose monitoring (Second arm, Closed-loop study without mitigation module). Commercial insulin infusion systems and continuous glucose monitoring devices will be used.<br>Device: Open-loop insulin infusion system<br>* Standard subcutaneous insulin infusion based on the individual insulin sensibility. Commercial insulin infusion systems and continuous subcutaneous glucose monitoring devices will be used.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of hypoglycaemias | Number of hypoglycemic episodes (defined as plasma glucose (PG) <70mg/dL) during exercise and recovery. | 180 minutes psot-exercise period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (area under curve) of PG during exercise and recovery | AUC0_180min, AUC0_60min and AUC60_180min of PG and time spent in different glycemic ranges (< 70; 70-180; > 180 mg/dL) during exercise and recovery. | 180 minutes post-exercise period | 
| AUC of SG during exercise and recovery | AUC0-180min, AUC0-60min and AUC60-180min of sensor glucose (SG) and time spent in different glycemic ranges (< 70; 70-180; > 180 mg/dL) during exercise and recovery. | 180 minutes post-exercise period | 
| Rate-of-change of glucose during exercise (ROCe) and recovery (ROCr) |  | 180 minutes post-exercise period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 1, Insulin, Exercise, Closed-loop, Artificial Pancreas