Individualizing Automated Closed Loop Glucose Control Through Pharmacokinetic Profiling in an Insulin-Only Bionic Pancreas

The investigators hypothesize that differences in the PK characteristics of insulin analogs
will lead to differences in glycemic outcomes when delivered by the insulin-only
configuration of the bionic pancreas. Specifically, the investigators predict that insulin
analogs that have faster absorption (numerically lower Tmax and/or T½max) and insulin analogs
that have faster clearance (numerically lower terminal half-life) will result in lower mean
glucose and/or a lower percentage of time in the hypoglycemic range.

Up to 30 subjects will participate in three 7-day study arms using insulin lispro, insulin
aspart, and BC222 lispro in the bionic pancreas in random order. The co-primary outcomes will
be mean CGMG and fraction of time spent with CGMG <54 mg/dl with comparisons made between
arms for individual participants. Secondary analyses will include time in glycemic ranges
(<50, <60, <70, 70-120, 70-180, >180, >250 mg/dl), coefficient of variation, mean
postprandial excursion (difference in CGMG from the time of meal announcement to the peak
CGMG in the first 4 hours after the meal announcement) for both mixed meal challenges, number
of symptomatic hypoglycemic events, grams of carbohydrate consumed to treat hypoglycemia, and
TDD of insulin, between arms for individual subjects.

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 at least one cumulative month over the last 12 months

- 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)

- Willing to remain within a 250 mile radius of MGH. No air travel will be allowed, and
subjects will still be expected to follow the visit schedule as described.

- Willing to wear one Dexcom CGM sensor, and one leur-lock compatible infusion set that
must be replaced every other day

- Have a mobile phone they will have access to at all times during the study 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)

- Renal failure requiring dialysis

- Estimated Glomerular filtration rate <15 mL/min/1.732

- 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 stroke15. Recent history of diabetic ketoacidosis (DKA) or severe
hypoglycemia in the last 6 months. Severe hypoglycemia is defined as an event that
required assistance of another person due to altered consciousness, and required
another person to actively administer carbohydrate, glucagon, or other resuscitative
actions. This means that the participant was impaired cognitively to the point that
he/she was unable to treat himself/herself, was unable to verbalize his/ her needs,
was incoherent, disoriented, and/or combative, or experienced seizure or coma.

- History of more than 1 episode of DKA requiring hospitalization in the last 2 years

- History of more than 1 episode of severe hypoglycemia in the last year.

- 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

- 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

- Any diagnosed allergy to insulin lispro or insulin aspart

- Lives in or frequents areas with poor Verizon wireless network coverage (which would
prevent study staff from contacting subjects)

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