Efficacy of Glucagon In the Prevention of Hypoglycemia During Mild Exercise

Twenty subjects will participate in two experimental periods. Each will include a 24-96 hour
outpatient run-in period prior to their exercise visit wearing the bi-hormonal bionic
pancreas. This will allow the bionic pancreas to adapt to their diabetes management needs.
After the run-in period is complete, the subjects will participate in an exercise visit
during which they will arrive fasting and remain fasted until the visit is completed.
Subjects will walk on a treadmill for up to 1 hour at a comfortable walking pace. Plasma
glucose (PG) measurements will be performed frequently. In one experimental period the bionic
pancreas will remain in the bihormonal configuration and will deliver glucagon as needed
during the exercise visit. In the other experimental period the glucagon will be replaced
with a placebo during the exercise visit. The two experimental periods will be performed in
random order. The study will be performed in single-blind fashion in that the participant
will not know whether the bionic pancreas glucagon pump is filled with glucagon or placebo
during the exercise visits. The outpatient run-in period will always be with the bi-hormonal
bionic pancreas delivering glucagon.

Inclusion Criteria:

- Age ≥ 18 years and have had clinical type 1 diabetes for at least one year

- Diabetes managed using an insulin pump for ≥ 6 months

- Have used a CGM for ≥ 4 weeks over the last 12 months (usage does not need to be
consecutive)

- 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 120 minute radius of Massachusetts General Hospital

- Willing to remain within a 250 mile radius of the central monitoring location during
the outpatient run-in period. No air travel will be allowed, and subjects will still
be expected to follow the visit schedule as described.

- Willing to spend the night prior to both exercise visits in a hotel and fast overnight
prior to exercise

- Willing to wear two steel cannula infusion sets (6 mm Contact Detach) and one Dexcom
CGM sensor and change sets frequently (a new glucagon infusion set daily and a new
insulin infusion set every other day during the outpatient run-in period)

- Have a mobile phone they will have access to at all times during the outpatient run-in
period for making contact with 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

- Subjects must use acceptable contraception for the two weeks prior to the study,
throughout the study and for the two weeks following the study.

- Acceptable contraception methods include:Oral contraceptive pill (OCP),
Intrauterine Device (IUD, hormonal or copper), Male condoms, Female condoms,
Diaphragm or cervical cap with spermicide, Contraceptive patch (such as
OrthoEvra), Contraceptive implant (such as Implanon, Nexplanon), Vaginal ring
(such as NuvaRing), Progestin shot (such as Depo-Provera), Male partner with a
vasectomy proven to be effective by semen analysis

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

- 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 or other
central nervous system depressants, 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 requiring dialysis

- Personal history of cystic fibrosis, severe pancreatitis, pancreatic tumor,
pancreatectomy or any other pancreatic disease leading to diabetes mellitus.

- 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:

- Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension

- Paroxysms of tachycardia, pallor, or headache

- Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or von
Hippel-Lindau disease

- Adrenal tumor that has not undergone characterization for endocrine function

- 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

- Use of oral (e.g. thiazolidinediones, biguanides, sulfonylureas, glitinides, DPP-4
inhibitors, SGLT-2 inhibitors) or non-insulin injectable (GLP-1 agonists, amylin)
anti-diabetic medications

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

- Hemoglobin < 12 g/dl for men, < 11 g/dl for women

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