New Strategies for Postprandial Glycemic Control Using Insulin Pump Therapy
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1
Intervention: iBolus; tBolus (traditional bolus)
Intervention description: Insulin bolus calculated from data obtained through CGM; Insulin bolus dose calculated using the standard procedure based on the insulin-to-carbohydrate ratio
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: T1DM; CSII; CGM; postprandial control; glycemic variability; Prandial insulin dosing in Type 1 diabetes treated with continuous subcutaneous insulin infusion

Summary:

      Achieving near-normoglycemia has been established as the main objective for most patients
      with type 1 diabetes (T1DM). However, insulin dosing is an empirical process and its success
      is highly dependent on the patients' and physicians' skills, either with multiple daily
      injections (MDI) or with continuous subcutaneous insulin infusion (CSII, the gold standard of
      insulin treatment).

      Postprandial glucose control is one of the most challenging issues in the everyday diabetes
      care. Indeed, postprandial glucose excursions are the major contributors to plasma glucose
      (PG) variability of subjects with (T1DM) and the poor reproducibility of postprandial glucose
      response is burdensome for both patients and healthcare professionals.

      During the past 10-15 years, there has been an exponentially increasing intrusion of
      technology into diabetes care with the expectation of making life easier for patients with
      diabetes. Some tools have been developed to aid patients in the prandial bolus
      decision-making process, i.e. "bolus advisors", which have been implemented in insulin pumps
      and more recently in the newest generations of glucometers. Currently, the availability of
      continuous glucose monitoring (CGM) has opened new scenarios for improving glycemic control
      and increasing understanding of post-prandial glycemic response in patients with diabetes.

      Results from clinical studies suggest that sensor-augmented pumps (SAP)may be effective in
      improving metabolic control, especially when included as part of structured educational
      programs resulting in patients' empowerment. Similarly, preliminary results from pilot
      studies indicate that automated glycemic control, especially during nighttime,based on
      information from CGM is feasible. However, automatic management of meal bolus is currently
      one of the main challenges found in clinical validations of the few existing prototypes of an
      artificial pancreas. Indeed, fully closed-loop systems where information about meals size and
      timing is not given to the system have shown poor performance, with postprandial glucose
      higher and post meal nadir glucose lower than desired. This has promoted other less-ambitious
      approaches, where prandial insulin is administered following meal announcement (semi
      closed-loop). However, despite the use of meal announcement, currently used algorithms for
      glucose control (the so-called PID and MPC), show results that are not yet satisfactory due
      to the risk of producing hypoglycemia.

      One of the limitations of the current open-loop (bolus advisors) and closed-loop control
      strategies is that glycemic variability is not taken into account. As an example, settings of
      CSII consider inter-individual variation of the parameters (insulin/carbohydrates ratio,
      correction dose, etc.) but disregard the day-to-day intra-individual variability of
      postprandial glucose response. Availability of massive amount of information from CGM,
      together with mathematic tools, may allow for the characterization of the individual
      variability and the development of strategies to cope with the uncertainty of the glycemic
      response to a meal.

      In this project, a rigorous clinical testing of a CGM-based, user-independent algorithm for
      prandial insulin administration will be carried out in type 1 diabetic patients treated with
      insulin CSII.

      First of all, an individual patient's model characterizing a 5-hour postprandial period will
      be obtained from a 6-day CGM period. The model will account for a 20% uncertainty in insulin
      sensitivity and 10% variability in the estimation of the ingested carbohydrates. Based on
      this model (derived from CGM), a mealtime insulin dose will be calculated (referred as
      iBolus). Then, the same subjects will undergo standardized meal test studies comparing the
      administration of a traditional bolus (tBolus, based on insulin to CHO ratio, correction
      factor, etc.) with the CGM-based prandial insulin delivery (iBolus).

      Significant advances in postprandial control are expected. Should its efficiency be
      demonstrated clinically, the method could be incorporated in advanced sensor augmented pumps
      as well as feedforward action in closed-loop control algorithms for the artificial pancreas,
      in future work.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Aged between 18 and 60 years

          -  Under CSII treatment for at least six months before Visit 1

          -  Body mass index of between 18 and 35 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), with a
             negative urine pregnancy tests

        Exclusion Criteria:

          -  Pregnancy and lactation

          -  History of hypersensitivity to the study medications or to drugs with similar chemical
             structures

          -  Hypoglycemia 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, 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.