Improving Postprandial Glycaemia by a New Developed Closed-loop Control System - Closedloop4meals

Improving Postprandial Glycaemia by a New Developed Closed-loop Control System (Closedloop4meals). An Interdisciplinary, Investigator's Initiated Project for Optimization of Glucose Control in Type1 Diabetic Subjects

Achieving near-normoglycemia has been established as the main objective for most patients with diabetes. However, postprandial glucose control is a challenging issue in everyday diabetes care. Indeed, excessive postprandial glucose excursions are the major contributors to plasma glucose (PG) variability in subjects with type 1 diabetes (T1DM). In addition, the poor reproducibility of postprandial glucose response is burdensome for patients and healthcare professionals.

Automatic glucose control, the so-called artificial pancreas 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 postprandial closed-loop control of blood glucose. Indeed, the eating process 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 and MPC) showed that closed-loop insulin delivery often tend to overcorrect hyperglycemia thus increasing the risk hypoglycemia.

In this project, a rigorous clinical testing of a novel closed-loop controller ('artificial pancreas') will be carried out in T1DM 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 (in simulation studies) to limit over-insulinization and the resulting hypoglycemia, reducing glycaemic variability.

Standardized meal test studies will be performed in T1DM subjects treated with CSII, comparing the administration of a classical bolus (open-loop study) with a controller-driven prandial insulin delivery (closed-loop study) based on continuous subcutaneous glucose monitoring (CGM).

The hypothesis is that closed loop control will provide better postprandial control, especially in terms of reduction of glucose variability and incidence of hypoglycemia.

Inclusion Criteria:

• Subjects with type 1 diabetes mellitus
• Continuous subcutaneous insulin infusion (CSII) treatment for at least six months before Visit 1
• Body mass index of between 18 and 30 kg/m2
• HbA1c 6.0-8.5% at Visit 1
• Normal laboratory values, ECG, and vital signs unless the investigator considered an abnormality to be clinically irrelevant
• Women postmenopausal or using contraception judged by the investigator to be adequate (e.g., oral contraceptives, intra-uterine device or surgical treatment), or with a negative negative urine pregnancy tests at visits 1, 3 and 5

Exclusion Criteria:

• Pregnancy and lactation
• History of hypersensitivity to the study medications or to drugs with similar chemical structures
• Hypoglycaemia unawareness
• Progressive fatal diseases
• History of drug or alcohol abuse
• History of positive HIV or hepatitis B or C test
• Impaired hepatic function, as shown by, but not limited to, SGPT or SGOT of more than twice the upper limit of the normal range at visit 1
• Impaired renal function, as shown by, but not limited to, serum creatinine > 1.5 mg/dL at visit 1
• Clinically relevant microvascular (pre-proliferative and proliferative retinopathy and macroalbuminuria), cardiovascular, hepatic, neurologic, endocrine or other major systemic diseases other than T1DM which could hinder implementation of the clinical study protocol or interpretation of the study results
• Pre-planned surgery during the study
• Blood donation of more than 500 ml during the past three months for men, or during the past six months for women
• Mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study
• Subject unlikely to comply with clinical study protocol, e.g., uncooperative attitude, inability to return for follow-up visits, or poor likelihood of completing the study
• Receipt of an experimental drug or use of an experimental device during the past 30 days.