Post Bariatric Closed Loop Glucagon Trial

Study Overview
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Brief Summary
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This study is to test our automated hypoglycemia prevention and treatment device (glucagon-only bionic pancreas) in subjects that have undergone post-bariatric surgery that are experiencing symptoms of hypoglycemia.

Official Title
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Closed-Loop Glucagon Administration For The Automated Treatment Of Post-Bariatric Hypoglycemia

Conditions
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Hypoglycemia

Intervention / Treatment
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* Device: Glucagon-only bionic pancreas - glucagon
* Device: Glucagon-only bionic pancreas - placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21 years or older with a gastric bypass for more than 1 year. Post-bariatric hypoglycemia with prior episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index, controlled carbohydrate portions) and trial of acarbose therapy at the maximally tolerated dose. Other therapies will not exclude a subject as long as the therapy is continued during the study. Otherwise healthy (mild chronic disease such as asthma, hypertension, and depression will be allowed if well controlled). Self-reported frequency of documented hypoglycemia (BG < 60 mg/dl verified by capillary blood glucose measurements) of at least 2 times per week. Exclusion Criteria: Unable to provide informed consent. Unable to comply with study procedures. Current participation in another hypoglycemia related clinical trial other than one that is primarily observational in nature. Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception. Use of insulin and/or insulin secretogues as sulfonylurea, metglitides, and glitazones. History of cystic fibrosis, pancreatitis, type 1 diabetes or other pancreatic disease. End stage renal disease on dialysis (hemodialysis or peritoneal dialysis). Any known liver or biliary disease including cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, any form of viral hepatitis. Congestive heart failure (established history of CHF, paroxysmal nocturnal dyspnea, or orthopnea). Acute illness or exacerbation of chronic illness at the time of the study. Known insulinoma or predominantly fasting pattern of hypoglycemia Adrenal insufficiency. Congenital hyperinsulinemia presenting with hypoglycemia during infancy. History of pheochromocytoma. Fractionated metanephrines will be tested in patients with history increasing the risk for a catecholamine secreting tumor: Paroxysms of tachycardia, pallor, or headache. Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease. Episodic or treatment refractory (requiring 4 or more medications to achieve normotension) hypertension. Untreated or inadequately treated mental illness (indicators would include symptoms such as psychosis, hallucinations, mania, and/or any psychiatric hospitalization in the last year). Current alcohol abuse (intake averaging > 3 drinks daily in last 30 days) or substance abuse (any use within the last 6 months of controlled substances without a prescription). Unwilling or unable to refrain from drinking more than two drinks in an hour or more than four drinks in a day during the trial. Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be susceptible to RF interference. History of adverse reaction to glucagon (including allergy) besides nausea and vomiting. Unwilling or unable to completely avoid acetaminophen during the study period. Any factors that, in the opinion of the principal investigator, would interfere with the safe completion of the study procedures.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glucagon-only bionic pancreas - glucagon<br>Subjects will wear the bionic pancreas that consists of a continuous glucose monitor linked to a smartphone running a hypoglycemia prevention algorithm that doses glucagon from an insulin pump through a subcutaneous infusion set. Subjects will continue to manage any hypoglycemia that occurs according to the current recommendations of their care provider. | Device: Glucagon-only bionic pancreas - glucagon<br>* A computer algorithm will automatically deliver glucagon based on the signal from a minimally invasive continuous glucose monitor.<br>|
| Placebo Comparator: Glucagon-only bionic pancreas - placebo<br>Subjects will wear the bionic pancreas that consists of a continuous glucose monitor linked to a smartphone running a hypoglycemia prevention algorithm that doses placebo from an insulin pump through a subcutaneous infusion set. Subjects will continue to manage any hypoglycemia that occurs according to the current recommendations of their care provider. | Device: Glucagon-only bionic pancreas - placebo<br>* A computer algorithm will automatically deliver placebo based on the signal from a minimally invasive continuous glucose monitor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Over the Curve and <60 mg/dl (CGM) Measured in mg/dl *Min | The measure for area over the curve is used when an integrated assessment (e.g., a measurement of something over a specific amount of time) is more useful in understanding a phenomenon. To calculate this measure, a method of approximation is often used. One way would be to estimate the curve via curve-fitting techniques. For this outcome, using area over the curve and <60mg/dl provides a more robust method of calculating amount of hypoglycemia (by including more severe degrees of hypoglycemia in the product of mg/dl*min as opposed to percentage of time below 60mg/dl. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Continuous Glucose Monitor (CGM) Glucose |  | 2 weeks | 
| Percentage of Time With CGM Glucose Less Than 60 mg/dl Overnight (11:00 PM - 7:00 AM) |  | 14 days | 
| Percentage of Time With CGM Glucose Less Than 60 mg/dl During Daytime ( 7:00 AM-11:00 PM) |  | 14 days | 
| Percentage of Time Spent Within the Glucose Range 70-120 mg/dl |  | 14 days | 
| Percentage of Time Spent Within the Glucose Range 70-180 mg/dl |  | 14 days | 
| Percentage of Time Spent Within the Glucose Range >180 mg/dl |  | 14 days | 
| Fraction of Time Spent Within the Glucose Range >250 mg/dl |  | 2 weeks | 
| Mean Absolute Relative Deviation (MARD) of CGM vs. All StatStrip Xpress BG Measurements | MARD is computed using the difference between the CGM readings and the values measured at the same time by the reference measurement system. The mean (or average) of all the absolute relative deviations produces the MARD. In this study, the reference measurement system was the StatStrip Xpress meter, to which the CGM values were compared. | 14 days | 
| Number of Carbohydrate Interventions for Hypoglycemia Per Day | Number of carbohydrate interventions for hypoglycemia per day calculated from daily email survey | 14 days | 
| Total Number of Grams of Carbohydrate Taken for Hypoglycemia Per Day | Calculated from daily email survey | 14 days | 
| Total Glucagon Dosing (mcg/kg/24 Hours) |  | 2 weeks | 
| Number of Symptomatic Hypoglycemia Events Per Day | Number of symptomatic hypoglycemia events per day calculated from daily email survey | 14 days | 
| Percentage of Days When Participants Correctly Guessed Intervention (Glucagon vs Placebo) Out of a Total of 14 Days. |  | 2 weeks | 
| Number of Days With Nausea | Number of days with nausea calculated from daily survey | 14 days | 
| Severity of Nausea on Daily E-mail Survey | The visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. We used a simple VAS is a straight horizontal line of fixed length measuring 0-100mm with subscale markings every 10mm. The ends are defined as the extreme limits of the parameter to be measured (nausea) orientated from the left (least severity or 0) to the right (most severity or 100mm). Subjects can mark their response anywhere from 0 to 100mm. The mean severity of nausea for the group in each arm was calculated by averaging all responses in either arm. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucagon, continuous glucose monitorering (CGM), artificial pancreas, hypoglycemia, post-bariatric hypoglycemia, bionic pancreas, bariatric surgery