Type 1 Diabetes
Conditions
Keywords
diabetes, glucose, hyperglycemia, hypoglycemia, insulin, glucagon, counter-regulation, closed-loop, feedback, control, dual-infusion, subcutaneous, automated, artificial pancreas, intensive insulin therapy
Brief summary
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.
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.
Interventions
DEVICEClosed-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
Sponsors
Massachusetts General Hospital
Juvenile Diabetes Research Foundation
Boston University Charles River Campus
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Average Blood Glucose Over the Closed-loop Control Period | 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 24 hours | This outcome captures the number of hypoglycemic events that occurred throughout the entire study |
| 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 | 24 hours | Time to maximum peak glucagon concentration |
| 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 | — |
| 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 | 24 hours | 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 |
| 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 | 24 hours | 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 |
| Set Point Using CGM Data as the Input to the Controller for Future Studies | 24 hours | 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. |
| 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 | — |
| Total Glucagon Dose | 24 hours | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Closed-loop Type 1 diabetic subjects under closed-loop blood glucose control
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 | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Closed-loop |
|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 16 |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 |
Outcome results
Primary
Average Blood Glucose Over the Closed-loop Control Period
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Average Blood Glucose Over the Closed-loop Control Period | 164 mg/dl | Standard Deviation 17 |
Secondary
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
Time frame: 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Closed-loop | Accuracy of the Continuous Glucose Monitor (CGM) Using Blood Glucose Measurement as the Standard | Navigator CGM | 9.94 percent absolute difference | Standard Deviation 10.09 |
| Closed-loop | Accuracy of the Continuous Glucose Monitor (CGM) Using Blood Glucose Measurement as the Standard | Dexcom CGM | 22.55 percent absolute difference | Standard Deviation 20.75 |
| Closed-loop | Accuracy of the Continuous Glucose Monitor (CGM) Using Blood Glucose Measurement as the Standard | Guardian CGM | 18.04 percent absolute difference | Standard Deviation 15.46 |
Secondary
Average Glucose and Glycemic Variability During Closed Loop Control in Diabetic Subjects Compared to the Comparable 24 Hour Period in Non-diabetic Subjects
Time frame: 24 hours
Population: This outcome was not analyzed. There were no experiments in non-diabetic subjects that we were able to make a comparison with
Secondary
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
Time frame: 24 hours
Population: Navigator CGM data from the day prior to admission was not obtained
Secondary
Blood Glucagon Levels
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Blood Glucagon Levels | 1.7 microgram/kg | Standard Deviation 0.36 |
Secondary
Glucagon T-max
Time to maximum peak glucagon concentration
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Glucagon T-max | 23 minutes | Standard Deviation 9 |
Secondary
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
Time frame: 24 hours
Population: This outcome was not analyzed. There were no experiments in non-diabetic subjects that we were able to make a comparison with
Secondary
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
Time frame: 24 hours
Population: This outcome was not analyzed. There were no open loop experiments in diabetic subjects that we were able to make a comparison with
Secondary
Nadir Blood Glucose Level for Each Hypoglycemic Event
Time frame: 24 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Closed-loop | Nadir Blood Glucose Level for Each Hypoglycemic Event | Event 1 of 2 | 66 mg/dl |
| Closed-loop | Nadir Blood Glucose Level for Each Hypoglycemic Event | Event 2 of 2 | 68 mg/dl |
Secondary
Number of Carbohydrate Interventions
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Closed-loop | Number of Carbohydrate Interventions | 0 number of interventions |
Secondary
Number of Hypoglycemic Events
This outcome captures the number of hypoglycemic events that occurred throughout the entire study
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Closed-loop | Number of Hypoglycemic Events | 2 Number of events |
Secondary
Number of Participants Achieving a Stable Glucose Response to Insulin Dosing
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Closed-loop | Number of Participants Achieving a Stable Glucose Response to Insulin Dosing | 11 participants |
Secondary
Number of Participants Achieving a Stable Glucose Response to Insulin Dosing Around Idle Times Prior to Meals
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Closed-loop | Number of Participants Achieving a Stable Glucose Response to Insulin Dosing Around Idle Times Prior to Meals | 11 participants |
Secondary
Peak Hyperglycemia Following Each Meal
Time frame: After each of 3 meals
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Closed-loop | Peak Hyperglycemia Following Each Meal | Breakfast | 226.7 mg/dl | Standard Deviation 26.6 |
| Closed-loop | Peak Hyperglycemia Following Each Meal | Lunch | 256.7 mg/dl | Standard Deviation 30.7 |
| Closed-loop | Peak Hyperglycemia Following Each Meal | Dinner | 276.5 mg/dl | Standard Deviation 33.8 |
Secondary
Percentage of Peak Post-prandial Hyperglycemias < 180 mg/dl (ADA Target)
Time frame: 24 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Closed-loop | Percentage of Peak Post-prandial Hyperglycemias < 180 mg/dl (ADA Target) | Breakfast | 6 percentage of blood glucose measurements |
| Closed-loop | Percentage of Peak Post-prandial Hyperglycemias < 180 mg/dl (ADA Target) | Lunch | 0 percentage of blood glucose measurements |
| Closed-loop | Percentage of Peak Post-prandial Hyperglycemias < 180 mg/dl (ADA Target) | Dinner | 0 percentage of blood glucose measurements |
Secondary
Percentage of Time Spent in Hyperglycemia (BG> 180 mg/dl) After Meals
Time frame: After each of 3 meals
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Percentage of Time Spent in Hyperglycemia (BG> 180 mg/dl) After Meals | 38 percentage of time | Standard Deviation 9 |
Secondary
Percentage of Time Spent With BG > 180 mg/dl
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Percentage of Time Spent With BG > 180 mg/dl | 38 percentage of time | Standard Deviation 2.9 |
Secondary
Percentage of Time Spent With BG < 70 mg/dl
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Percentage of Time Spent With BG < 70 mg/dl | 0.35 percentage of time | Standard Deviation 0.33 |
Secondary
Percentage of Time Spent Within 70-180 mg/dl
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Percentage of Time Spent Within 70-180 mg/dl | 61 percentage of time | Standard Deviation 15 |
Secondary
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
Time frame: 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Dexcom < 70 | 18.90 percent absolute difference | Standard Deviation 11.85 |
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Navigator < 70 | 18.64 percent absolute difference | Standard Deviation 16.96 |
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Guardian < 70 | 36.46 percent absolute difference | Standard Deviation 23.6 |
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Dexcom > 180 | 20.28 percent absolute difference | Standard Deviation 15.34 |
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Navigator > 180 | 9.41 percent absolute difference | Standard Deviation 8.78 |
| Closed-loop | Sensitivity for Hypo- and Hyperglycemia of the CGM Devices Using the BG Measurement as the Standard | Guardian > 180 | 20.71 percent absolute difference | Standard Deviation 16.95 |
Secondary
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.
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Closed-loop | Set Point Using CGM Data as the Input to the Controller for Future Studies | 100 mg/dl |
Secondary
Total Glucagon Dose
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Total Glucagon Dose | 3.5 mcg/kg | Standard Deviation 2.8 |
Secondary
Total Insulin Dose
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Closed-loop | Total Insulin Dose | 0.67 u/kg | Standard Deviation 0.34 |