Type 1 Diabetes
Conditions
Keywords
Physiologic Insulin Delivery (PID), Closed Loop, Sensor, Insulin sensitivity
Brief summary
The purpose of this study is to test the ability of an advanced external Physiologic Insulin Delivery (ePID) algorithm (a step by step process used to develop a solution to a problem) to get acceptable meal responses over a range of gain. Gain is defined as how much insulin is given in response to a change in a patient's glucose level. This study also examines the effectiveness of the external Physiologic Insulin Delivery (ePID) closed-loop insulin delivery computer software. The investigators would like to assess whether fasting target levels can be achieved as the closed-loop gain increases or decreases, and to evaluate the system's ability to produce an acceptable breakfast meal response.
Detailed description
There have been significant advances in diabetes management technology, including more sophisticated insulin pumps and more accurate real-time continuous glucose monitors. The next technological development is widely thought to be the introduction of an algorithm linking the pump and sensor to form a closed-loop insulin delivery system. The algorithm used for this purpose needs to be robust to changes in an individual's insulin sensitivity, and the sensor's sensitivity to glucose. Insulin sensitivity (how much the patient's glucose level changes in response to a change in insulin delivery) and algorithm gain (how much insulin is delivered in response to a change in glucose) determine the systems overall closed-loop gain. Ideally, the overall gain can be set to achieve the lowest possible peak postprandial glucose response without postprandial hypoglycemia. However, if the algorithm's gain is set to a fixed value and the subject's insulin sensitivity changes, the overall-gain will change. Some degradation in closed-loop performance might be acceptable during periods whenever the subject's insulin sensitivity is low (i.e., the subject is insulin resistant) and the risk of hypoglycemia may actually be reduced. However, if the subject becomes more sensitive the system may become less stable and the risk of postprandial hypoglycemia may increase. In addition to changes in insulin sensitivity, glucose sensors will sometimes over- or under-read blood glucose as sensor sensitivity increases or decreases. This will result in a change in the closed-loop algorithm's effective target. The purpose of this study is to evaluate the ability of an advanced Physiologic Insulin Delivery algorithm to achieve an acceptable breakfast response as the gain and effective target glucose level changes. Specifically: 1. to assess the fasting glucose levels achieved as the overall closed-loop gain and effective target is increased or decreased, and 2. determine the system's ability to produce an acceptable breakfast meal response under these conditions
Interventions
DEVICEHIGH error
Overnight and breakfast closed-loop control were performed using a target glucose of 120 mg/dL but with the glucose-value-used-for-control equal to 1.33 times the true glucose value (analogous to higher gain lower target).
DEVICENO error
Overnight and breakfast closed-loop control were performed using a target glucose of 120 mg/dL and glucose-value-used-for-control equal to the true glucose value.
DEVICELOW error
Overnight and breakfast closed-loop control were performed using a target glucose of 120 mg/dL but with the glucose-value-used-for-control equal to 0.8 times the true glucose value (analogous to lower gain higher target).
Sponsors
Juvenile Diabetes Research Foundation
Joslin Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Study subjects are studied under closed-loop control on three occasions: once with the glucose values used for control equal to blood glucose (NO error), once with values 33% higher than blood glucose (HIGH error), and once with values 20% lower than blood glucose (LOW error). The six different sequences of these three exposures then comprise the six arms of this crossover study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes for \> 3 years * Manage diabetes using a continuous glucose monitor and continuous subcutaneous insulin infusion pump * Non obese (BMI \< 30) * Aged 18 - 75 years old * HbA1c \< 8 %
Exclusion criteria
* renal or hepatic failure * cancer or lymphoma * Malabsorption or malnourishment * Hypercortisolism * Alcoholism or drug abuse * Anemia (hematocrit \< 36 in females and \<40 in males) * Eating disorder * Dietary restrictions * Acetaminophen allergy * Chronic acetaminophen use * Glucocorticoid therapy * History of gastroparesis * Use of Beta blockers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Area Under the Curve (AUC) Breakfast | On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 2:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors | Glucose Area Under the Curve (AUC) Breakfast defines the total exposure to glucose during breakfast. Breakfast is typically considered the most difficult meal to control; low AUC is desirable.This outcome measure was analyzed for each of the three calibration error values (high error, no error and low error). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak and Nadir Postprandial Glucose Concentration | On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 12:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors | Highest and lowest glucose concentrations obtained during breakfast meal. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL) | On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 12:00 AM to 6:00 AM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors | Night-time in target range 5.0-8.33, following the 3 hour controller initialization period blood glucose remained at or near target. |
Countries
United States
Participant flow
Recruitment details
Written informed consent was obtained from all 8 participants at the Joslin Diabetes Center. All study related activities were conducted at the Center for Clinical Investigations at the Beth Israel deaconess Medical Center.
Participants by arm
| Arm | Count |
|---|---|
| Closed-loop Control Closed-loop control was performed from 9:00 PM to 2:00 the day following admission on three occasions: once with a glucose-value-used-for control calculated to be higher than the true blood glucose (analogous to a sensor glucose signal that is miss-calibrated); once with the value equal to blood glucose (analogous to a sensor signal with no calibration), and once with the value calculated to be lower than blood glucose. Six different arms were utilized, defined by the differing sequences of each of the three values used for control (no error, high error and low error previously defined). On each occasion control was separated into the nighttime period (midnight to 08:00 AM) and breakfast period (8:00 AM to 2:00 PM). | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Scheduling conflicts | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Closed-loop Control |
|---|---|
| Age, Continuous | 57 years |
| Daily insulin use | 35.4 units/day |
| HbA1c | 7.7 % |
| Median duration of diabetes | 47 years |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 |
Outcome results
Primary
Glucose Area Under the Curve (AUC) Breakfast
Glucose Area Under the Curve (AUC) Breakfast defines the total exposure to glucose during breakfast. Breakfast is typically considered the most difficult meal to control; low AUC is desirable.This outcome measure was analyzed for each of the three calibration error values (high error, no error and low error).
Time frame: On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 2:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HIGH Error | Glucose Area Under the Curve (AUC) Breakfast | 66.8 mmol/l/min |
| NO Error | Glucose Area Under the Curve (AUC) Breakfast | 48.8 mmol/l/min |
| LOW Error | Glucose Area Under the Curve (AUC) Breakfast | 37.4 mmol/l/min |
Comparison: Differences among the 3 groups were assessed by repeated measures ANOVA using Sidak's correction for multiple comparisons. All subjects were analyzed as a single group, no comparison group.p-value: 0.001195% CI: [33.4, 80.3]ANOVA
Secondary
Peak and Nadir Postprandial Glucose Concentration
Highest and lowest glucose concentrations obtained during breakfast meal.
Time frame: On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 12:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
Population: Analysis was limited to the 5 subjects completed all aspects of the study per protocol (i.e. 5 subjects who completed all three scheduled breakfast meals).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| HIGH Error | Peak and Nadir Postprandial Glucose Concentration | Peak glucose concentration | 13.3 mmol/l |
| HIGH Error | Peak and Nadir Postprandial Glucose Concentration | Nadir glucose concentration | 4.5 mmol/l |
| NO Error | Peak and Nadir Postprandial Glucose Concentration | Peak glucose concentration | 11.8 mmol/l |
| NO Error | Peak and Nadir Postprandial Glucose Concentration | Nadir glucose concentration | 4.8 mmol/l |
| LOW Error | Peak and Nadir Postprandial Glucose Concentration | Peak glucose concentration | 11.3 mmol/l |
| LOW Error | Peak and Nadir Postprandial Glucose Concentration | Nadir glucose concentration | 6.6 mmol/l |
p-value: 0.0059ANOVA
Other Pre-specified
Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL)
Night-time in target range 5.0-8.33, following the 3 hour controller initialization period blood glucose remained at or near target.
Time frame: On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 12:00 AM to 6:00 AM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
Population: Analysis was limited to the 6 subjects completing all 3 nighttime periods per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIGH Error | Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL) | 88 percentage of time in target range |
| NO Error | Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL) | 100 percentage of time in target range |
| LOW Error | Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL) | 80 percentage of time in target range |