The Set-Point Study: Evaluating Effects of Changing Glucose Target on Bionic Pancreas Performance

We have two specific aims:

Aim 1 is to conduct an outpatient study testing multiple configurations of the bionic
pancreas in 24 adult subjects with type 1 diabetes in a random cross-over study versus usual
care with an insulin pump. These bionic pancreas configurations include the insulin only BP
at 145 mg/dl set point, 130 mg/dl set point, 120 mg/dl set point and 110 mg/dl set point and
the bihormonal BP at 130 mg/dl set point, 115 mg/dl set point and 110 mg/dl set point. These
arms are all compared to usual care.

Aim 2 is to evaluate the incremental utility of glucagon in the context of automated insulin
delivery by the bionic pancreas in preventing hypoglycemia during exercise in the fasted
state. The 130 mg/dl set points and 110 mg/dl set points also participate in this fasted
exercise visit. These two set points are double blinded, so neither the subjects nor the
study staff are aware which arm is bihormonal and which arm is insulin only.

Inclusion Criteria:

Type 1 Diabetes Subjects: Age ≥ 18 years and have had clinical type 1 diabetes for at least
one year, and managed using an insulin pump for ≥ 6 months Type 2 Diabetes subjects: Age ≥
18 years and have type 2 diabetes managed with rapid acting insulin in an insulin pump, or
multiple daily injections including both long acting and short acting insulin

- Prescription medication regimen stable for > 1 month (except for medications that will
not affect the safety of the study and are not expected to affect any outcome of the
study, in the judgment of the principal investigator)

- Live within a 60 minute drive-time radius of the central monitoring location

- Willing to remain within a 120 minute drive-time radius of the central monitoring
location throughout the study

- Have someone over 18 years of age who lives with them, has access to where they sleep,
is willing to be in the house when the subject is sleeping, and is willing to receive
calls from the study staff and check the welfare of the study subject if telemetry
shows a technical problem or severe biochemical hypoglycemia without subject response
and the subject does not answer their telephone (up to two individuals can share this
role, but they must be willing to carefully coordinate with each other and the subject
so that one of them is clearly designated as having this responsibility at any given
time)

- Willing to wear two infusion sets and one CGM sensor and change sets frequently (at
least one new glucagon infusion set daily during bi-hormonal arms, and insulin
infusion set every other day throughout the study)

- Have a mobile phone they are willing to keep with them and answer calls from study
staff

Exclusion Criteria:

- Unable to provide informed consent (e.g. impaired cognition or judgment)

- Unable to safely comply with study procedures and reporting requirements (e.g.
impairment of vision or dexterity that prevents safe operation of the bionic pancreas,
impaired memory, unable to speak and read English)

- Current participation in another diabetes-related clinical trial that, in the judgment
of the principal investigator, will compromise the results of this study or the safety
of the subject

- Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the
immediate future, or sexually active without use of contraception

- Need to go outside of the designated geographic boundaries during the study

- Current alcohol abuse (intake averaging > 3 drinks daily in last 30 days), use of
marijuana within 1 month of enrollment, or other substance abuse (use within the last
6 months of controlled substances other than marijuana without a prescription)

- Unwilling or unable to refrain from drinking more than 2 drinks in an hour or more
than 4 drinks in a day or use of marijuana during the trial

- Unwilling or unable or to avoid use of drugs that may dull the sensorium, reduce
sensitivity to symptoms of hypoglycemia, or hinder decision making during the period
of participation in the study (use of beta blockers will be allowed as long as the
dose is stable and the subject does not meet the criteria for hypoglycemia unawareness
while taking that stable dose, but use of benzodiazepines or narcotics, even if by
prescription, may be excluded according to the judgment of the principal investigator)

- History of liver disease that is expected to interfere with the anti-hypoglycemia
action of glucagon (e.g. liver failure or cirrhosis). Other liver disease (i.e. active
hepatitis, steatosis, active biliary disease, any tumor of the liver, hemochromatosis,
glycogen storage disease) may exclude the subject if it causes significant compromise
to liver function or may do so in an unpredictable fashion.

- Renal failure on dialysis

- Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides type 1 diabetes

- Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)

- Abnormal EKG consistent with coronary artery disease or increased risk of malignant
arrhythmia including, but not limited to, evidence of active ischemia, prior
myocardial infarction, proximal LAD critical stenosis (Wellen's sign), prolonged QT
interval (> 440 ms). Non-specific ST segment and T wave changes are not grounds for
exclusion in the absence of symptoms or history of heart disease. A reassuring
evaluation by a cardiologist after an abnormal EKG finding may allow participation.

- Congestive heart failure (established history of CHF, lower extremity edema,
paroxysmal nocturnal dyspnea, or orthopnea)

- History of TIA or stroke

- Seizure disorder, history of any non-hypoglycemic seizure within the last two years,
or ongoing treatment with anticonvulsants

- History of hypoglycemic seizures (grand-mal) or coma in the last year

- History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:

oEpisodic or treatment refractory (requiring 4 or more medications to achieve normotension)
hypertension oParoxysms of tachycardia, pallor, or headache oPersonal or family history of
MEN 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease

- History of adrenal disease or tumor

- Hypertension with systolic BP ≥160 mm Hg or diastolic BP ≥100 despite treatment

- Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the
last year), or treatment with anti-psychotic medications that are known to affect
glucose regulation.

- Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be
susceptible to RF interference

- Unable to completely avoid acetaminophen for duration of study

- History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting

- Established history of allergy or severe reaction to adhesive or tape that must be
used in the study

- History of eating disorder within the last 2 years, such as anorexia, bulimia, or
diabulemia or omission of insulin to manipulate weight

- History of intentional, inappropriate administration of insulin leading to severe
hypoglycemia requiring treatment

- Type 1 diabetes subjects: Use of oral (e.g. thiazolidinediones, biguanides,
sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) anti-diabetic
medications

- Type 2 diabetes subjects: Use of oral anti-diabetic medications other than metformin

- Lives in or frequents areas with poor Verizon wireless network coverage (which would
prevent remote monitoring)

- Any factors that, in the opinion of the principal investigator would interfere with
the safe completion of the study