Safety and Feasibility of an Insulin Sensitivity-Informed Bolus Calculator in Type 1 Diabetes

Individuals with Type 1 Diabetes (T1D) require exogenous insulin to keep their blood glucose
concentration in a safe euglycemic range, because of the absent internal insulin secretion
caused by the autoimmune destruction of pancreatic beta-cells. As a consequence, the quality
of glycemic control in T1D is heavily dependent on multiple daily treatment decisions by the
patients, which are complicated by a wide variety of factors influencing insulin demand
(e.g., circadian rhythms, physical activity, food, stress, etc.). Insulin sensitivity (SI) is
a key metabolic parameter in diabetes as it informs on how sensitive the body is to the
effects of insulin. In general, if someone has higher SI, the amount of insulin required to
lower his blood glucose levels is smaller than that needed by someone who has low
sensitivity. However, SI levels within the same person are not constant, and fluctuations of
SI happen very frequently in the life of subjects with diabetes, making insulin dosing very
difficult to tune.

In this context, the aim of this research project is to develop an SI-informed insulin bolus
calculator, with the aim of tailoring the insulin dose to the individual's insulin need at
the time the bolus is administered. The SI-informed bolus calculator relies on a Kalman
filter-based algorithm which uses continuous glucose monitoring (CGM) data, insulin, and meal
records to estimate SI. For each subject, a 24-hour SI profile is computed using data
collected over several days of monitoring, and the optimal bolus is then computed by
adjusting the standard insulin dose by the ratio between usual SI (from the profile) and
real-time SI of the individual at the time the bolus is administered. In this way, if the
real-time SI is larger/smaller than the profile SI at that time of day, the insulin dose will
be reduced/incremented accordingly.

The study is thus designed as a single-center randomized clinical trial targeting completion
of 15 subjects, who will undergo a 28-day at home Data Collection Period followed by two
24-hour admissions (Control and Experimental Admission) performed in random order in a
semi-controlled environment (i.e., hotel). The Data Collection is meant to collect data
needed to build the 24-hour SI profile for the subject. During the admissions, subjects will
undergo a 45-minute afternoon exercise session designed to alter the late-afternoon/evening
SI. The dinner meal will then be controlled, and the postprandial glycemic control obtained
using the standard bolus calculator (Control Admission) will be compared to the control
obtained in response to the optimized SI-informed bolus calculator (Experimental Admission).
Metrics computed on CGM data will be compared between the two admissions, including mean
blood glucose, time above 250 and 300 mg/dL, time below 70 and 54 mg/dL, and time in 70-180
mg/dL, the primary outcome being the postprandial exposure to hypoglycemia as measured by the
Low Blood Glucose Index (a glycemic variability indicator which summarizes the number and
extent of low blood glucose events in one single number). If successful, this study will
provide a novel, data-oriented paradigm for insulin dosing in T1D.

Inclusion Criteria:

1. Type 1 diabetes for at least 12 months

2. Current use of an insulin pump for at least 12 months

3. Current or historical use of a CGM system for at least 6 months

4. Age ≥18 to ≤65 years old

5. HbA1c <8.5% at screening; if HbA1c <6.0% then total daily insulin must be ≥0.5 U/kg

6. For females, not currently known to be pregnant. If female and sexually active, must
agree to use a form of contraception to prevent pregnancy while a participant in the
study. A negative urine pregnancy test will be required for all premenopausal women
who are not surgically sterile. Subjects who become pregnant will be discontinued from
the study

7. Willingness to use the same set of insulin therapy parameters (i.e., basal rate,
insulin-to-carbohydrate ratio, correction factor) during both admissions

8. Willingness to upload data during the study

9. An understanding of and willingness to follow the protocol and sign the informed
consent

Exclusion Criteria:

1. Diabetes ketoacidosis (DKA) in the 6 months prior to enrollment

2. Clinically significant electrocardiogram (ECG) found at Screening as determined by the
study medical physician

3. Severe hypoglycemia resulting in seizure or loss of consciousness in the 6 months
prior to enrollment

4. Currently being treated for a seizure disorder

5. Coronary artery disease or heart failure, unless written clearance is received from a
cardiologist or primary care provider and documentation of a negative stress test
within the year

6. History of cardiac arrhythmia (except for benign premature atrial contractions and
benign premature ventricular contractions which are permitted)

7. Cystic fibrosis

8. Pregnancy, breast-feeding, or intention of becoming pregnant over time of study
procedures

9. Abnormal liver function test results (Transaminase >2 times the upper limit of normal)

10. Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2)

11. Uncontrolled thyroid disease (TSH undetectable or >10 mIU/L)

12. A known medical condition that in the judgment of the investigator might interfere
with the completion of the protocol such as the following examples:

- Inpatient psychiatric treatment in the past 6 months for either the subject or
the subject's care companion

- Presence of a known adrenal disorder

- Active gastroparesis

- If on antihypertensive, thyroid, anti-depressant or lipid lowering medication,
lack of stability on the medication for the past 2 months prior to enrollment in
the study

13. Abuse of alcohol or recreational drugs

14. Infectious process not anticipated to resolve prior to study procedures (e.g.
meningitis, pneumonia, osteomyelitis)

15. Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or
systolic blood pressure >160 mmHg)

16. A recent injury to body or limb, muscular disorder, use of any medication, any
carcinogenic disease, or other significant medical disorder if that injury, medication
or disease in the judgment of the investigator will affect the completion of the
protocol

17. Basal Rate <0.01 units/hour

18. Inability to be physically active for more than 30 minutes per day

19. Conditions that would make use of a CGM difficult (e.g., blindness, severe arthritis,
immobility)

20. Current enrollment in another intervention clinical trial

List any restrictions on use of other drugs or treatments:

1. Medications being taken to lower blood glucose, such as Pramlintide, Metformin, GLP-1
Analogs such as Liraglutide, and nutraceuticals intended to lower blood glucose

2. Any other medication that the investigator believes is a contraindication to the
subject's participation