Three Way Crossover Closed Loop Study With Xeris Glucagon
Three Way Crossover Closed Loop Study With Xeris Glucagon
Closed-loop systems are an emerging technology that automate hormone delivery. They are
 quickly paving the way to revolutionize the treatment of type 1 diabetes. Several categories
 have emerged: dual-hormone (insulin and glucagon) closed-loop systems and closed-loop systems
 with insulin only, one variety of which is the low glucose suspend safety feature now
 available from Medtronic (MiniMed640G with SmartGuard). The study described within this
 protocol is designed to test the efficacy of a new closed-loop algorithm for managing blood
 glucose in people with type 1 diabetes before and after exercise. The new algorithm will have
 3 modes: a single hormone insulin only mode, a dual-hormone insulin and glucagon mode and an
 insulin only mode with predictive low glucose suspend, all with an exercise detection
 algorithm. The purpose of this study is to determine whether a dual hormone AP using a stable
 investigational glucagon with an exercise detection algorithm outperforms both single hormone
 AP and a low glucose suspend algorithm.
Subjects will undergo three approximately 76 hour studies. During each of these intervention
 visits, subjects will wear an Omnipod to deliver insulin and a Dexcom G5 CGM to measure
 glucose. In the dual-hormone closed-loop study, participants will wear a second Omnipod
 filled with XeriSol™ glucagon. The first day of intervention visit will be a 12 hour
 inpatient visit with the subsequent time spent as an outpatient. The subject will come back
 to the research center on Day 4 in the morning to remove all devices. The blood glucose
 control system is called the Artificial Pancreas Controller (APC). During one of the studies,
 glucose will be controlled using the dual hormone mode. During another study, glucose will be
 controlled using the single hormone mode. The single and dual hormone modes of the APC
 controller determine insulin only and insulin with glucagon delivery rates based on
 proportional and derivative error and contain an exercise detection component. During the
 other study, glucose will be controlled using a predictive low glucose suspend (PLGS) mode.
 In the PLGS mode, the APC will be programmed with the subject's basal profile(s) which will
 be transmitted to the Omnipod Personal Diabetes Manager (PDM) and allow for boluses to be
 inputted by the subjects for meals and corrections using their typical carb ratios and
 correction factors. However, this system will have a safety feature to suspend insulin
 delivery when sensor glucose is predicted to go below a threshold. Treatment order will be
 randomized.

 Subjects will arrive at the clinic at approximately 7 or 8am for the inpatient visits.
 Subjects will eat breakfast and lunch at approximately 8:30am, noon and 6pm respectively. The
 dinner meal will be consumed while the subject is at home. Subjects will exercise on a
 treadmill for 45 minutes. Subjects will be discharged 9 hours after admission. The subject
 will then go home for the remainder of the study visit. Studies will be remotely monitored.
 Subjects will return to OHSU on Day 4 for removal of all devices.

 During each study, the subject will wear one subcutaneous DexcomTM G5 continuous glucose
 monitoring (CGM) system. The CGM system will provide sensed glucose data every 5 minutes. The
 accuracy of the sensed data will be obtained by reference measurements of capillary blood
 glucose. Sensed glucose data will be wirelessly transmitted via Bluetooth Low Energy (BTLE)
 from the Dexcom G5 transmitter to the Nexus 5 master controller every five minutes. The
 controller for all 3 modes is a Google Nexus 5 phone. The smart phone will wirelessly
 communicate via BTLE to an Omnipod through a PDM (Insulet Corp. ) for automated insulin
 delivery or in the case of dual-hormone AP, one used for automated insulin delivery and one
 for automated glucagon delivery.

 A physician or nurse practitioner will be present for study start-up, will be on campus for
 exercise on Day 1 and will be immediately available on call at all other times.
Inclusion Criteria:

 -  Diagnosis of type 1 diabetes mellitus for at least 1 year.

 -  Male or female subjects 21-50 years of age.

 -  Physically willing and able to perform 45 min of exercise.

 -  Current use of an insulin pump.

 -  Lives with another person age 18 or older who will be present while subject exercises
 at home and that can attend the training on using the system.

 -  Lives within 40 miles of OHSU main campus.

 -  HbA1c <= 10% at screening.

 -  Total daily insulin requirement is less than 139 units/day.

 -  Current use of a phone or other device so can be contacted by study staff off-campus.

 -  Willingness to follow all study procedures, including attending all clinic visits.

 -  Willingness to sign informed consent and HIPAA documents.

 Exclusion Criteria:

 -  Female of childbearing potential who is pregnant or intending to become pregnant or
 breast-feeding, or is not using adequate contraceptive methods. Acceptable
 contraception includes birth control pill/patch/vaginal ring, Depo-Provera, Norplant,
 an IUD, the double barrier method (the woman uses a diaphragm and spermicide and the
 man uses a condom), or abstinence.

 -  Any cardiovascular disease, defined as a clinically significant EKG abnormality at the
 time of screening or any history of: stroke, heart failure, myocardial infarction,
 angina pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd
 and 3rd degree heart block or any non-physiological arrhythmia judged by the
 investigator to be exclusionary.

 -  Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as report by the OHSU
 laboratory).

 -  Liver failure, cirrhosis, or any other liver disease that compromises liver function
 as determined by the investigator.

 -  Hematocrit of less than 36% for men, less than 32% for women.

 -  Hypertensive subjects with systolic blood pressure >= 160 mm Hg or diastolic blood
 pressure >= 100 mm Hg despite treatment or who have treatment-refractory hypertension
 (e.g. requiring four or more medications).

 -  History of severe hypoglycemia during the past 12 months prior to screening visit or
 hypoglycemia unawareness as judged by the investigator. Subjects will complete a
 hypoglycemia awareness questionnaire. Subjects will be excluded for four or more R
 responses.

 -  Adrenal insufficiency.

 -  Any active infection.

 -  Known or suspected abuse of alcohol, narcotics, or illicit drugs.

 -  Seizure disorder.

 -  Active foot ulceration.

 -  Severe peripheral arterial disease characterized by ischemic rest pain or severe
 claudication.

 -  Major surgical operation within 30 days prior to screening.

 -  Use of an investigational drug within 30 days prior to screening.

 -  Chronic usage of any immunosuppressive medication (such as cyclosporine, azathioprine,
 sirolimus, or tacrolimus).

 -  Bleeding disorder, treatment with warfarin, or platelet count below 50,000.

 -  Allergy to aspart insulin.

 -  Allergy to glucagon.

 -  Need for uninterrupted treatment of acetaminophen.

 -  Current administration of oral or parenteral corticosteroids.

 -  Any life threatening disease, including malignant neoplasms and medical history or
 malignant neoplasms within the past 5 years prior to screening (except basal and
 squamous cell skin cancer).

 -  Beta blockers or non-dihydropyridine calcium channel blockers.

 -  Current use of any medication intended to lower glucose other than insulin (e.g. use
 of liraglutide).

 -  Diagnosis of pheochromocytoma, insulinoma, or glucagonoma, personal or family history
 of multiple endocrine neoplasmia (MEN) 2A, MEN 2B, neurofibromatosis or von
 Hippel-Lindau disease.

 -  History of severe hypersensitivity to milk protein.

 -  Current use of any medication with strong anticholinergic properties, such as
 antihistamines, sleep aids, and antidiarrheal medications.

 -  Current use of indomethacin.

 -  Conditions that may results in low levels of releasable glucose in the liver and an
 inadequate reversal of hypoglycemia by glucagon such as prolonged fasting, starvation
 or chronic hypoglycemia as determined by the investigator.

 -  A positive response to any of the questions from the Physical Activity Readiness
 Questionnaire with one exception: subject will not be excluded if he/she takes a
 single blood pressure medication that doesn't impact heart rate and blood pressure is
 controlled on the medication (blood pressure is less than 140/90 mmHg).

 -  Any chest discomfort with physical activity, including pain or pressure, or other
 types of discomfort.

 -  Any clinically significant disease or disorder which in the opinion of the
 investigator may jeopardize the subject's safety or compliance with the protocol.