Hybrid Closed Loop Insulin Delivery System in Hypoglycemia

The purpose of this small, proof-of-concept, mechanistic study is to determine whether hybrid
closed-loop insulin delivery can achieve sufficient hypoglycemia avoidance in patients with
long standing type 1 diabetes experiencing hypoglycemia and symptom unawareness despite
receiving intensive insulin therapy standard-of-care to improve glucose counterregulation
against insulin-induced hypoglycemia. As it remains critically important to understand the
potential physiologic benefits of hypoglycemia avoidance by means of a hybrid closed-loop
system in this population, studying each well characterized subject as his/her own control by
a within subject design should serve the study purpose, and has been the standard approach to
assessing the effects of various approaches to hypoglycemia avoidance in patients with
unawareness. The data generated will be available to power future randomized clinical trials
to determine the comparative efficacy of emerging artificial pancreas and β-cell replacement
approaches to achieve target glycemic control with amelioration of problematic hypoglycemia
in type 1 diabetes.

Screening Phase At the screening visit, the study details and procedures will be discussed
with a research coordinator and at least one of the PI or the research nurse practitioner.
The potential participant is given adequate time to ask questions and review the informed
consent document. Once satisfied that all questions have been answered, the potential
participant will either decline to participate or sign the informed consent document. This
may occur at a subsequent visit if the potential participant desires, in order to think
further about what participation means and/or to consult with family, friends and/or a
personal physician. The consent form is signed in the presence of a witness (research
coordinator +/- family member). All participants must read, sign, and date a consent form
before entering the study, undergoing physical examination or undergoing any testing. The
informed consent form will be revised whenever important new safety information is available,
whenever the protocol is amended, and/or whenever any new information becomes available that
may affect participation in the studies.Eligibility will be confirmed through the performance
of a history and physical examination by the PI or the research nurse practitioner, EKG,
urine pregnancy test (if applicable), serum chemistries, TSH, cell counts, HbA1c and
C-peptide, completion of glycemic lability and hypoglycemia awareness and hypoglycemia
severity questionnaires, placement of a 7 day blinded CGM (iPro 2, Medtronic Diabetes,
Northridge, CA) unless on CGM available for downloading, and 7 day accelerometry (WGT3X-BT,
Actigraph LLC,) to define the nocturnal period.

Only after all eligibility criteria (inclusion and exclusion) are met, will a potential
subject be enrolled. Repeated clinical testing throughout the study will ensure the continued
safety and minimization of risk for the enrolled participants.

Study Intervention Phase Eligible subjects will complete a baseline assessment of glucose
counterregulation by stepped- hyperinsulinemic hypoglycemic clamp prior to starting
intervention with the hybrid closed-loop system (MiniMed 670G system, Medtronic Diabetes,
Northridge, CA). Unless this system becomes available to the subject via their insurance
carrier, one will be provided for them. Subjects will also receive a study glucometer
(Contour Next Link 2.4, Bayer, Indianapolis, IN) that communicates with the MiniMed 670G
insulin pump for bolus dosing calculation and glucose sensor calibration. Subjects who cannot
maintain > 80% (or 6/7 day) compliance with the sensor component as assessed at each study
visit may be dropped since less compliance has not been associated with any benefit of CGM to
glycemic control and limits the potential for benefit from LGS on hypoglycemia avoidance.
Accuracy of the sensor will be assessed at each visit through devise download and
interpretation. Study visits will occur weekly for the first month, then monthly until month
6, and then every 3 months until month 18. This schedule will allow for determination of
possible benefit from hybrid closed- loop insulin delivery on glucose counterregulation after
6 months of intensive provider support, and then for assessment of the durability or
potential further gains in beneficial effects after another 12 months of more typical
provider interaction occurring every 3 months. Weekly visits may be performed via telephone
with uploading devise data to Care Link for review and interpretation. Uploaded or downloaded
insulin delivery, blood and sensor glucose monitoring, insulin dose settings and CGM
calibration accuracy, alert settings, time spent in auto and manual modes, and LGS threshold
and activity will be assessed at each visit, targeting > 80% CGM and LGS compliance,
adjusting basal and bolus insulin dosing in order to minimize glycemic excursions while
maximizing hypoglycemia (< 60 mg/dl) avoidance, with adjustment of alarms set to alert the
subject to rapidly increasing or decreasing glucose and predict the occurrence of elevated or
low blood glucose. During manual mode, target glucose ranges will be 90 - 140 mg/dl before
meals, < 180 mg/dl after meals, and 120 - 160 mg/dl at bedtime, with correction dosing to no
lower than 100 mg/dl during the day, and 120 mg/dl overnight. Alarm settings may be
individualized to target these ranges, but the hypoglycemia alarm for LGS will not be set
lower than 70 mg/dl. During auto mode, the automated interprandial basal insulin delivery
will adjust according to the closed-loop algorithm to target a sensor glucose of 120 mg/dl,
which may be temporality increased to 150 mg/dl if needed to further minimize exposure to
hypoglycemia during exercise or overnight. Prior to each 3 monthly visit, subjects will wear
an actigraph monitor ( WGT3X-BT, Actigraph LLC,) for three weeks in order to define the
nocturnal period. Every 6 months measures of hypoglycemia awareness (Clarke score) and
severity (HYPO score), and the glycemic lability index (LI) will be calculated from
questionnaires, event diaries, and device downloads, respectively. At 6 months and at 18
months, subjects will again undergo assessment of glucose counterregulation by
stepped-hyperinsulinemic hypoglycemic clamp testing.

Inclusion Criteria:

- Male and female subjects age 25 to 70 years.

- Subjects who are able to provide written informed consent and to comply with the
procedures of the study protocol.

- Clinical history compatible with type 1 diabetes with disease onset < 40 years of age
and insulin dependent for > 10 years.

- Absent C-peptide (< 0.3 ng/ml).

- Involvement in intensive diabetes management defined as the use of basal-bolus insulin
analog delivery by multi-dose injection (MDI) or continuous subcutaneous insulin
infusion (CSII) together with self-monitoring of blood glucose values more than 3
times daily with or without continuous glucose monitoring (CGM) under the direction of
an endocrinologist, diabetologist, or diabetes nurse practitioner with at least 3
clinical evaluations during the previous 12 months.

- Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least 1 of
the following: HYPO score greater than or equal to the 90th percentile (1047); OR
marked glycemic lability defined by a glycemic lability index (LI) score greater than
or equal to the 90th percentile (433 mmol/l2/h•wk-1); OR a composite of a HYPO score
greater than or equal to the 75th percentile (423) and a LI greater than or equal to
the 75th percentile (329) (Senior et al., 2015).

- Documented > 5% time spent in the hypoglycemic range (glucose < 60 mg/dl) by 7 day
real- time or blinded CGM; at least one episode of hypoglycemic during the 7 days must
occur overnight.

Exclusion Criteria:

- BMI ≥ 30 kg/m2.

- Insulin requirement of ≥ 1.0 units/kg•day.

- HbA1c ≥ 10%.

- Untreated proliferative diabetic retinopathy.

- Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood
pressure > 100 mmHg.

- Active cardiovascular disease

- Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.

- Abnormal liver function: persistent elevation of liver function tests > 1.5 times the
upper limit of normal.

- Untreated hypothyroidism, Addison's disease, or Celiac disease.

- Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.

- Presence of a seizure disorder not related to prior severe hypoglycemia.

- Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent
physiologic dose of hydrocortisone.

- For female participants of child-bearing potential: Positive pregnancy test, presently
breast-feeding, or unwillingness to use effective contraceptive measures for the
duration of study participation. Oral contraceptives, intra-uterine devices,
Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable
contraceptive methods; condoms used alone are not acceptable.

- Treatment with any anti-diabetic medication other than insulin within 4 weeks of
enrollment.

- Use of any investigational agents within 4 weeks of enrollment.

- Any medical condition that, in the opinion of the PI, will interfere with the safe
completion of the study