Closed-loop Glucose Control for Automated Management of Type 1 Diabetes

We hypothesize that our integrated closed-loop glucose-control system can provide effective, tight, and safe blood glucose (BG) control in type 1 diabetes, thereby establishing the feasibility of closed-loop BG control.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Device: Closed-loop

Detailed Description

This study investigates the utility of an integrated closed-loop glucose-control system for regulating BG in type 1 diabetic subjects. The closed-loop system utilizes sub-cutaneous infusion or insulin and glucagon under the control of a computer algorithm. The only inputs to the algorithm are the subject weight and BG values measured every five minutes. Subjects will undergo up to three 27 hour GCRC admissions during which they will consume three standardized meals. Subject may participate in up to two closed-loop visits (with different insulin lispro pharmacokinetic parameter settings in the control algorithm) and some subjects will participate in open-loop visits. During the closed-loop admission BG will be controlled by the closed-loop system. During the open-loop visit subjects will regulate their own BG in the usual function using their insulin pumps. A small group of non-diabetic subjects will undergo a single 27 hour GCRC admission during which they will eat the same standardized meals. During all admission BG will be measured every 5 minutes and blood will be collected for measurement of insulin and glucagon levels every 10 minutes. During the closed-loop admission of diabetic subjects and the single admission of non-diabetic subjects, three commercially available continuous glucose monitoring devices will be worn. The data from these devices will later be compared to reference BG data.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (type 1 diabetic subjects):

• Age 18 years or older
• Clinical type 1 diabetes for at least five years
• Otherwise healthy (mild chronic disease allowed if well controlled)
• Diabetes managed using an insulin infusion pump
• Body mass index (BMI) between 20 and 31
• Total daily dose (TDD) of insulin ≤ 1 U/kg and ≤ 100 U/day
• Post-prandial C-peptide < 0.1 nmol/L at 90 minutes in a mixed meal (Sustacal) tolerance test by the DCCT method
• Hemoglobin A1c less than or equal to 8.5%
• Prescription medication regimen stable for at least 1 month

Inclusion Criteria (non-diabetic subjects):

• Age 18 years or older
• No personal history of diabetes, impaired fasting glucose, or impaired glucose tolerance
• No personal history of pancreatic disease
• Not taking medication that may affect glucose, insulin, or glucagon dynamics
• Otherwise healthy (mild chronic disease allowed if well controlled)
• Body mass index (BMI) between 20 and 31
• Normal 75 g oral glucose tolerance test (fasting, 1 hour, and 2 hour measurements)

Exclusion Criteria (all subjects):

• Unable to provide informed consent or are unable to comply with study procedures
• Current participation in another clinical trial
• Anemia (HCT or hemoglobin less than normal for sex)
• Elevated alanine aminotransferase (ALT > 3 fold above upper limit of normal)
• Untreated or inadequately treated hyperthyroidism or hypothyroidism (abnormal TSH or free T4)
• Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception
• Progressive or proliferative diabetic retinopathy (subjects with mild, non-proliferative background retinopathy or stable disease previously treated with photocoagulation are not excluded).
• Renal insufficiency (creatinine clearance estimated by Cockcroft-Gault equation of ≤ 50 ml/min)
• Any known history or symptoms of coronary artery disease.
• Abnormal EKG
• Congestive heart failure
• History of TIA or stroke within preceding 6 months
• Acute illness or exacerbation of chronic illness at the time of the study procedure
• Change in medication regimen in the 30 days prior to enrollment
• History of seizures
• History of pheochromocytoma
• Abnormal plasma fractionated metanephrines
• History of adrenal disease or tumor
• History of pancreatic tumor, including insulinoma
• History of impaired gastric motility or gastroparesis requiring pharmacological or surgical treatment
• Current alcohol abuse (> 3 drinks daily) or substance abuse (any use within the last 6 months of illegal drugs)
• Severe mental illness (schizophrenia, bipolar disease, inadequately treated depression, or any psychiatric hospitalization in the last year)
• Impaired cognition or altered mental status.
• Hypertension (blood pressure > 140/90) at the time of screening
• Use of medications that reduce gastric motility
• Electrically powered implants that might be susceptible to RF interference
• Use non-insulin injectable anti-diabetic medications, inhaled insulin, or oral anti-diabetic medications
• History of adverse reaction to glucagon (including allergy) besides nausea and vomiting.
• Established history of latex, adhesive, tape allergy, inadequate venous access, history of allergy to or intolerance of aspirin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Closed-loop; Type 1 diabetic subjects under closed-loop blood glucose control	Device: Closed-loop; Computer algorithm developed by Firas El-Khatib and Edward Damiano at Boston University that controls sub-cutaneous infusion of insulin and glucagon to regulate blood glucose to target

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Average Blood Glucose Over the Closed-loop Control Period	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Time Spent Within 70-180 mg/dl		24 hours
Peak Hyperglycemia Following Each Meal		After each of 3 meals
Percentage of Time Spent in Hyperglycemia (BG> 180 mg/dl) After Meals		After each of 3 meals
Percentage of Peak Post-prandial Hyperglycemias < 180 mg/dl (ADA Target)		24 hours
Percentage of Time Spent With BG < 70 mg/dl		24 hours
Number of Hypoglycemic Events	This outcome captures the number of hypoglycemic events that occurred throughout the entire study	24 hours
Nadir Blood Glucose Level for Each Hypoglycemic Event		24 hours
Percentage of Time Spent With BG > 180 mg/dl		24 hours
Total Insulin Dose		24 hours
Glucagon T-max	Time to maximum peak glucagon concentration	24 hours
Total Glucagon Dose		24 hours
Blood Glucagon Levels		24 hours
Average Glucose and Glycemic Variability (MAGE) During Closed Loop Control in Diabetic Subjects Compared to the Comparable 24-hour Period the Day Prior to Admission as Measured by Navigator CGM Data		24 hours
Number of Carbohydrate Interventions		24 hours
Number of Participants Achieving a Stable Glucose Response to Insulin Dosing		24 hours
Number of Participants Achieving a Stable Glucose Response to Insulin Dosing Around Idle Times Prior to Meals		24 hours
Accuracy of the Continuous Glucose Monitor (CGM) Using Blood Glucose Measurement as the Standard	Measuring the mean absolute relative difference (MARD) between the blood glucose measurement and CGM glucose readings, on three different CGM devices: Dexcom, Guardian and Navigator	24 hours
Average Glucose and Glycemic Variability During Closed Loop Control in Diabetic Subjects Compared to the Comparable 24 Hour Period in Non-diabetic Subjects		24 hours
Insulin and Glucagon Levels During the Closed-loop Admission as Compared to the Comparable 24 Hour Period During the Open Loop Admission of Diabetic Subjects		24 hours
Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard	Mean absolute relative difference (MARD) of CGM and BG glucose readings in hypoglycemia (< 70 mg/dl) and hyperglycemia (>180 mg/dl) in three different CGM devices: Dexcom, Navigator and Guardian	24 hours
Set Point Using CGM Data as the Input to the Controller for Future Studies	The algorithm in the Bionic Pancreas must have a pre-specified target glucose it is trying to achieve in order to make dosing decisions. Using data from this study, investigators planned to determine what an appropriate glucose target should be for future studies.	24 hours
Insulin and Glucagon Levels During Closed Loop and Open Loop Admissions of Diabetic Subjects Compared to the Comparable 24 Hour Period During the Admission of Non-diabetic Subject		24 hours

Collaborators and Investigators

• Sponsor: Boston University Charles River Campus
• Collaborators: Massachusetts General Hospital; Juvenile Diabetes Research Foundation
• Investigators: Study Director: Steven J Russell, M.D., Ph.D., Massachusetts General Hospital; Principal Investigator: Edward Damiano, Ph.D., Boston University

Publications and helpful links

General Publications

• El-Khatib FH, Jiang J, Gerrity RG, Damiano ER. Pharmacodynamics and stability of subcutaneously infused glucagon in a type 1 diabetic Swine model in vivo. Diabetes Technol Ther. 2007 Apr;9(2):135-44. doi: 10.1089/dia.2006.0006.
• El-Khatib FH, Jiang J, Damiano ER. Adaptive closed-loop control provides blood-glucose regulation using dual subcutaneous insulin and glucagon infusion in diabetic Swine. J Diabetes Sci Technol. 2007 Mar;1(2):181-92. doi: 10.1177/193229680700100208.
• El-Khatib FH, Jiang J, Damiano ER. A feasibility study of bihormonal closed-loop blood glucose control using dual subcutaneous infusion of insulin and glucagon in ambulatory diabetic swine. J Diabetes Sci Technol. 2009 Jul 1;3(4):789-803. doi: 10.1177/193229680900300428.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: May 29, 2008
• First Submitted That Met QC Criteria: December 17, 2008
• First Posted (Estimate): December 18, 2008

Study Record Updates

• Last Update Posted (Actual): October 25, 2017
• Last Update Submitted That Met QC Criteria: October 24, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: diabetes; hypoglycemia; subcutaneous; glucagon; artificial pancreas; closed-loop; insulin; intensive insulin therapy; feedback; control; hyperglycemia; glucose; automated; counter-regulation; dual-infusion
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 2007P-000101; H-27207; SPID#0813

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: Yes