A Multicenter Study of Outpatient Automated Blood Glucose Control With a Bihormonal Bionic Pancreas

Study Overview
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Brief Summary
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This study will test the hypothesis that a wearable bionic pancreas system that automatically delivers insulin and glucagon can provide superior regulation of glycemia versus usual care for adults with type 1 diabetes. Please note that all participants must work or attend school at one of the following campuses: Massachusetts General Hospital in Boston, MA; University of Massachusetts Medical Center in Worcester, MA; University of North Carolina in Chapel Hill, NC; Stanford University in Palo Alto, CA.

Official Title
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A Multicenter Study of Outpatient Automated Blood Glucose Control With a Bihormonal Bionic Pancreas

Conditions
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Diabetes Mellitus Type 1

Intervention / Treatment
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* Device: Bionic Pancreas
* Device: Insulin pump with or without CGM


Participation Criteria
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Eligibility Criteria
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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 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 judgement of the site principal investigator). Employee or student working or studying during most of the week at one of the participating campuses (Massachusetts General Hospital in Boston, MA; University of Massachusetts Medical Center in Worcester, MA; University of North Carolina in Chapel Hill, NC; Stanford University in Palo Alto, CA) Lives within a 30 minute drive-time radius of the central monitoring location for one of the study sites Willing to remain within a 60 minute drive-time radius of the central monitoring location for one of the study sites during each of the 11-day study arms 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 continuous glucose monitor (CGM) sensor and change sets frequently (at least one new glucagon infusion set daily) 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 human chorionic gonadotropin (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 either arm of 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 electrocardiogram (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 left anterior descending coronary artery (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 (CHF) [established history of CHF, lower extremity edema, paroxysmal nocturnal dyspnea, or orthopnea] History of transient ischaemic attack (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 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 multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B), neurofibromatosis, or von Hippel-Lindau disease History of adrenal disease or tumor Hypertension with systolic blood pressure (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 radio-frequency (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 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 oral [e.g. thiazolidinediones, biguanides, sulfonylureas, glitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibitors] anti-diabetic medications Lives in or frequents areas with poor Verizon wireless network coverage (which would prevent remote monitoring) Any factors that, in the opinion of the site principal investigator or overall principal investigator, would interfere with the safe completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bionic Pancreas<br>Bionic Pancreas diabetes management, a wearable bionic pancreas system that automatically delivers insulin and glucagon using a continuous glucose monitoring (CGM) device, for 11 days. | Device: Bionic Pancreas<br> <br> |
| Active Comparator: Usual Care<br>Usual Care diabetes management, standard of care for diabetes including use of an insulin pump with or without CGM according to the participant's usual practice, for 11 days. | Device: Insulin pump with or without CGM<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Continuous Glucose Monitoring Glucose (CGMG) Values During Days 2 to 11 | Glucose reading were taken every 5 minutes by the CGM. The glucose results on Days 2 to 11 were averaged. | Days 2 to 11 of each period | 
| Percentage of Time Spent With CGMG Concentration < 60 mg/dL During Days 2 to 11 | Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than 60 mg/dL [3.3 millimoles/liter (mmol/L)] during Days 2 to 11 was calculated. | Days 2 to 11 of each period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean CGMG Values | Glucose reading were taken every 5 minutes by the CGM. The glucose results on Days 1 and Days 1 to 11 were averaged. | Day 1 and Days 1 to 11 in each period | 
| Percentage of Time With CGMG Concentration by Ranges During Day 1 | Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated: < 50 mg/dL (2.8 mmol/L) < 60 mg/dL (3.3 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L) | Day 1 of each period | 
| Percentage of Time With CGMG Concentration by Ranges During Days 1 to 11 | Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated: < 50 mg/dL (2.8 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L) | Days 1 to 11 of each period | 
| Percentage of Time With CGMG Concentration by Ranges During Days 2 to 11 | Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated: < 50 mg/dL (2.8 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L) | Days 2 to 11 of each period | 
| Percentage of Participants With Mean CGMG < 154 mg/dl | Glucose reading were taken every 5 minutes by the CGM. The glucose readings were averaged. 154 mg/dL was the estimated average glucose corresponding to a Glycosylated Hemoglobin A1C of 7%. | Day 1, Days 2 to11, Days 1 to11 of each period | 
| Number of Hypoglycemic Events (< 70 mg/dL, < 60 mg/dL, <50 mg/dL) | A series of hypoglycemic measurements is defined as a single event until there is a break of ≥ 30 minutes between measurements below the defined thresholds of < 70, < 60, and <50 mg/dL. | Days 1-11 | 
| Percentage of Days That CGM Was Used by Participants as Part of Their Usual Care | The percentage of days that participants reported the CGM device was being worn and working properly is reported. | Days 1-11 of each period | 
| Glycated Albumin on Day 12 |  | Day 12 of each period | 
| 1,5-anhydroglucitol on Day 12 |  | Day 12 of each period | 
| Anti-Insulin and Anti-Glucagon Antibodies on Day 12 |  | Day 12 of each period | 
| Number of Participants With Severe Hypoglycemic Events | A severe hypoglycemic event is an event where the participant is unable to self-treat and requires the assistance of another person. | 11 days of each period | 
| Number of Episodes of Symptomatic Hypoglycemia | The number of episodes of symptomatic hypoglycemia were reported daily by the participant. The average number of episodes of symptomatic hypoglycemia per day was calculated. | Day 1, Days 1 to 11 and Days 2 to 11 of each period | 
| Number of Reported Carbohydrate Interventions for Hypoglycemia | The number of carbohydrate interventions for hypoglycemia were reported daily by the participant. The average number of carbohydrate interventions per day is reported. | Day 1, Days 1 to 11 and Days 2 to 11 of each period | 
| Total Grams of Carbohydrate Taken for Hypoglycemia | The total grams of carbohydrate taken for hypoglycemia as reported daily by the participant were averaged. The total number of grams of carbohydrate taken for hypoglycemia were reported daily by the participant. The total number of grams of carbohydrate taken are reported. | Day 1, Days 1 to 11 and Days 2 to 11 of each period | 
| Insulin Total Daily Dose | Insulin total daily dose is reported in units per kilogram per day (U/kg/day). | Day 1, Days 1 to 11, Days 2 to 11 of each period | 
| Glucagon Total Daily Dose Levels in the Bionic Pancreas Arm | Glucagon dose level is reported in micrograms per kilogram of body mass per day (µg/kg/day). | Day 1, Days 2 to 11, Days 1 to 11 of each period | 
| Mean Glucose Target Set by User (Time-weighted Average Over Study Period) in the Bionic Pancreas Arm |  | Day 1, Days 2 to 11, Days 1 to11, Overall, Daytime, Nighttime of each period | 
| Percentage of Time Bionic Pancreas Off-line or Not Functioning Properly | Not functioning properly includes issues due to system crash, communication problems between CGM and bionic pancreas, communication problems between bionic pancreas and pumps and pump malfunction. | 11 days | 
| Mean Nausea Index Score Using a Visual Analog Scale (VAS) | Participants rated their nausea using a 0 to 10 centimeter (cm) VAS where 0=least severe nausea to 10=most severe nausea. The average nausea index scores during Days 1 to 11 and Days 2 to 11 were calculated. | Day 1, Days 1 to 11, Days 2 to 11 and each individual day 2 to 11 of each period | 
| Change From Baseline in Body Weight | The change in body weight collected at Day 12 relative to Baseline. A negative change from Baseline indicates a reduction in body weight and a positive change from Baseline indicates an increase in body weight. | Baseline and Day 12 of each period | 
| Change From Baseline in Hemoglobin | The change in the value of hemoglobin collected at Day 12 relative to Baseline. A negative change from Baseline indicates a reduction in hemoglobin and a positive change from Baseline indicates an increase in hemoglobin. | Baseline and Day 12 of each period | 
| Number of Participants With Skin Rash |  | 11 days of each period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bionic Pancreas, Insulin, Glucagon, Continuous Glucose Monitor