Type 1 Diabetes Mellitus
Conditions
Brief summary
In this protocol the investigators plan to demonstrate the feasibility of a modular insulin management system based on continuous glucose monitoring and targeted towards the avoidance of hypoglycemic and prolonged hyperglycemic episodes (i.e. control to range). The protocol is designed to challenge the insulin management system with meals and mild exercise, so as to demonstrate its capacity to avoid large glucose excursion with changing metabolic state. This system is designed to both * monitor the meal boluses of the patient and correct it in case of observed/predicted under insulinization (avoidance of prolonged hyperglycemia), based on a coarse and subjective knowledge of the meal amount, a precise understanding of the subject's day to day insulin treatment, continuous glucose monitoring, and past insulin injections; * predict and avoid hypoglycemic events, based on continuous glucose reading and past insulin injection. The investigators plan to enroll 12 adult Type 1 Diabetes Mellitus (T1DM) patients (expected retention 10/12) and compare glucose control performances under two treatments: standard vs. the new insulin management system. The protocol will include a total of 6 admissions per subject (4 out-patients and 2 in-patients): screening, effort test, CGM insertion 1, inpatient 1, CGM insertion 2, and inpatient 2. During the 24h inpatient admissions, the patients will be challenged with 30 minutes of mild exercise and 3 meals, insulin coverage of these events will vary depending on the chosen treatment, each subject will be exposed to both studied treatments (repeated measure design).The order of treatment during the inpatient admissions will be randomized.
Interventions
DEVICEClosed Loop Control (CLC)
In this study, the researchers compared the management of diabetes during physical activity and meals with the closed-loop system developed at the University of Virginia. This Control to Range System uses two DexCom Seven Continuous Glucose Monitor, a computer containing an investigational control algorithm (well-defined instructions that are expressed in mathematical equations), and an OmniPod Insulin Management System, a portable subcutaneous (under the skin) insulin pump. During the closed-loop admission, the computer used CGM values to make recommendations of insulin treatment based on the algorithms.
DEVICEOpen Loop
This admission was to assess the subjects' level of glucose control and created a base to compare the performance of the closed-loop system. Subjects monitored their own blood glucose values and administer their basal/bolus as they would at home. Subjects use their own pump. Otherwise, the admission remained the same as in the closed-loop admission (i.e. meals, exercise, etc...).
Sponsors
Abbott Diabetes Care
Insulet Corporation
DexCom, Inc.
University of California, Santa Barbara
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 21 years of age and up to and including 65 years of age. * Have Type 1 Diabetes Mellitus as defined by American Diabetes Association criteria or judgment of physician for at least 2 years (including those who may also be treated with metformin, thiazolidinedione, exenatide, or pramlintide). * Use of an insulin pump * If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, have stability on the medication for at least 2 months prior to enrollment in the study * Willingness to use lispro (Humalog) insulin for the duration of the inpatient study * Demonstration of proper mental status and cognition for the study * Willingness to stop using any dietary supplements for two weeks prior to admission and for the duration of their participation.
Exclusion criteria
* Age \<21or \>65 * Pregnancy * Hematocrit \<36% (females); \<38% (males) * HemoglobinA1c \> 10.0 * Symptomatic coronary artery disease (e.g. history of myocardial infarction, history of acute coronary syndrome, history of therapeutic coronary intervention, history of coronary bypass or stenting procedure, stable or unstable angina, episode of chest pain of cardiac etiology with documented EKG changes, positive stress test or catheterization with coronary blockages \>50%). * Use of a medication that significantly lowers heart rate (beta blockers, reserpine, guanethidine, methyldopa, clonidine, cimetidine, digitalis, calcium channel blockers, amiodarone, antiarrythmic drugs, or lithium) * Congestive heart failure * History of a cerebrovascular event * Use of a medication that significantly impacts glucose metabolism (oral steroids) * Atrial fibrillation * Uncontrolled hypertension (resting blood pressure \>140/90) * History of a systemic or deep tissue infection with methicillin- resistant staph aureus or Candida albicans * Use of a device that may pose electromagnetic compatibility issues and/or radiofrequency interference with the FreeStyle NavigatorTM CGM (implantable cardioverter-defibrillator, electronic pacemaker, neurostimulator,intrathecal pump, and cochlear implants) * Active enrollment in another clinical trial * Allergy or adverse reaction to lispro insulin * Known adrenal gland problem, pancreatic tumor, or insulinoma * Current alcohol abuse by patient history, substance abuse by patient history, or severe mental illness * Retinopathy and renal failure * Uncontrolled anxiety or panic disorder * Known bleeding diathesis or dyscrasia * Renal insufficiency (creatinine \>1.5) * Any comorbid condition affecting glucose metabolism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycemic Events | Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR | Number of hypoglycemic events below 70 mg/dL per patient per day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Time Spent in Near Normoglycemia | Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR | Comparison of time spent in near normoglycemia (3.9 to 10 mmol/mL) in open-loop vs closed-loop sCTR and eCTR. |
| Mean Glucose | Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR | Average plasma glucose concentration in mg/dl |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Control to Range (sCTR) The two modules of sCTR are the SSM and a standard range control module that avoids prolonged hyperglycemic excursions. Both modules use a real-time estimate of the patient 's metabolic state based on CGM and insulin infusion data. This estimate is used for prediction of the risks of hypo-and hyperglycemia 30-45 min ahead of the event. If a risk for hypoglycemia is predicted, the SSM attenuates automatically any insulin requests proportionally to the predicted risk level. How aggressively the system attenuates insulin is determined with patient characteristics (e.g., body weight, insulin-to-carbohydrate ratio, and basal insulin delivery). If a risk for hyperglycemia is predicted, the range controller gives a correction bolus using the predicted plasma glucose and the patient's CSII parameters; the system injects only half of the computed bolus and can do so once every hour. | 26 |
| Enhanced Control to Range (eCTR) The two modules of the eCTR are the SSM and an enhanced range control module based on an MPC algorithm that aims to maintain glycemia in a target range. eCTR also uses insulin-on-board constraints (29) intended to prevent insulin overdose during intensified therapy. The rationale behind MPC was presented in detail in a recent review (7). Controller aggressiveness was individualized for each subject based on readily available patient characteristics (e.g., body weight, insulin-to-carbohydrate ratio, and basal insulin delivery) (30). In this application, the MPC worked using information from the individual's conventional therapy. Premeal boluses were triggered by the patient, with the carbohydrate amount measured in the CRC kitchen but automatically calculated by eCTR. | 12 |
| Total | 38 |
Baseline characteristics
| Characteristic | Standard Control to Range (sCTR) | Enhanced Control to Range (eCTR) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 0 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Female | 11 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 15 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 38 | 2 / 26 | 0 / 12 |
| serious Total, serious adverse events | 0 / 38 | 0 / 26 | 0 / 12 |
Outcome results
Primary
Hypoglycemic Events
Number of hypoglycemic events below 70 mg/dL per patient per day
Time frame: Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Loop | Hypoglycemic Events | eCTR (N=12) | 1.4 events/admission per patient | Standard Deviation 0.56 |
| Open Loop | Hypoglycemic Events | sCTR (N=26) | 1.08 events/admission per patient | Standard Deviation 0.27 |
| Closed Loop | Hypoglycemic Events | eCTR (N=12) | 1.6 events/admission per patient | Standard Deviation 0.68 |
| Closed Loop | Hypoglycemic Events | sCTR (N=26) | 0.4 events/admission per patient | Standard Deviation 0.13 |
Secondary
Mean Glucose
Average plasma glucose concentration in mg/dl
Time frame: Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Loop | Mean Glucose | sCTR (N=26) | 8.82 mg/dL | Standard Deviation 0.54 |
| Open Loop | Mean Glucose | eCTR (N=12) | 7.74 mg/dL | Standard Deviation 0.44 |
| Closed Loop | Mean Glucose | sCTR (N=26) | 8.34 mg/dL | Standard Deviation 0.28 |
| Closed Loop | Mean Glucose | eCTR (N=12) | 6.68 mg/dL | Standard Deviation 0.28 |
Secondary
Percent Time Spent in Near Normoglycemia
Comparison of time spent in near normoglycemia (3.9 to 10 mmol/mL) in open-loop vs closed-loop sCTR and eCTR.
Time frame: Throughout each 22-hour closed-loop and open-loop admission for sCTR and eCTR
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Loop | Percent Time Spent in Near Normoglycemia | sCTR (N=26) | 61.5 percentage of time | Standard Deviation 5.2 |
| Open Loop | Percent Time Spent in Near Normoglycemia | eCTR (N=12) | 76.8 percentage of time | Standard Deviation 5 |
| Closed Loop | Percent Time Spent in Near Normoglycemia | sCTR (N=26) | 74.4 percentage of time | Standard Deviation 3.9 |
| Closed Loop | Percent Time Spent in Near Normoglycemia | eCTR (N=12) | 90.1 percentage of time | Standard Deviation 3.4 |