Pilot Study 3 of Outpatient Control-to-Range: Safety and Efficacy With Day-and-Night In-Home Use

Study Overview
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Brief Summary
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The purpose of this study is to see if an automated insulin management system (study system) can safely be used at home to manage blood sugar. The study system includes (1) a CGM that measures glucose levels, (2) a computer program on a smartphone that determines how much insulin is needed and allows the study participant user to control the whole system, and (3) an insulin pump that delivers the insulin. The CGM will be from Dexcom. The pump will be from Roche. The CGM and pump are similar to the devices that are currently available for people to purchase and use. However, the smartphone device, the CGM sensor type used with it, and the overall study system can only be used for research at this time. The study will be completed by about 24 individuals at 6 centers in the United States and Europe. This study has several phases and will take about 11-14 weeks to complete depending on whether the study participant is a CGM user or not. At selected sites (based on subject eligibility and availability), approximately 10-20 subjects who exhibit safe and competent use of the system at home will be given the option to continue home use of the system in Day-and-Night Closed-Loop mode for up to 5 months.

Detailed Description
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The study phases are as follows: Screening visit to see if you are eligible for the study and to determine how long you will need to use the study CGM (visit 1) Up to 3 weeks using the study CGM (depends on your current CGM use), followed by an office visit (visit 2) 2 weeks using the study insulin pump and study CGM together Full day visit in clinic or hotel for training using the system (visit 3) 1 week using the system without automated insulin delivery or suspension 2-day hotel or clinic visit for closed-loop training (visit 4), 16-19 days using the system in the evening and overnight only followed by an office visit (visit 5) 16-19 days using the system for the full 24 hours Final study clinic visit (visit 6) Option 5 month extension phase of day-and-night closed-loop home use

Official Title
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Pilot Study 3 of Outpatient Control-to-Range: Safety and Efficacy With Day-and-Night In-Home Use

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Device: Closed-Loop Control System
* Device: Sensor-Augmented Pump (SAP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year and using insulin for at least 1 year and an insulin pump for at least 6 months. Age >=18 to <70 years. HbA1c <10.0%; if HbA1c <6.0% then total daily insulin must be >=0.5 U/kg For females, not currently known to be pregnant. If female and sexually active, must agree to use a form of contraception to prevent pregnancy while a participant in the study. A negative urine pregnancy test will be required for all premenopausal women who are not surgically sterile. Subjects who become pregnant will be discontinued from the study. Demonstration of proper mental status and cognition for the study. Currently using insulin-to-carbohydrate ratio to calculate meal bolus sizes Hypoglycemia awareness as demonstrated by a Clarke Hypoglycemia Awareness score of 2 or lower Access to internet and cell phone service at home, and a computer for downloading device data. Living with significant other or family member committed to participating in all training activities, knowledgeable at all times of the participant's location, and being present and available to provide assistance when system is being used at night. Commitment to maintaining uninterrupted availability via cell phone and avoiding any overnight travel for the duration of each two-week period using the closed-loop system. An understanding of and willingness to follow the protocol and sign the informed consent. Exclusion Criteria: Admission for diabetic ketoacidosis in the 12 months prior to enrollment. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to enrollment. History of a seizure disorder (except hypoglycemic seizure), unless written clearance is received from a neurologist. Coronary artery disease or heart failure, unless written clearance is received from a cardiologist. History of cardiac arrhythmia (except for benign premature atrial contractions and benign premature ventricular contractions which are permitted) Cystic fibrosis. A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples: Inpatient psychiatric treatment in the past 6 months for either the subject or the subject's primary care giver (i.e., parent or guardian) Presence of a known adrenal disorder Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function Abnormal renal function test results (calculated GFR <60); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty Active gastroparesis If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study Uncontrolled thyroid disease (TSH undetectable or >10); testing required within three months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise Abuse of alcohol or recreational drugs Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis) 7. A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol 8. Current use of the following drugs and supplements: Acetaminophen Any medication being taken to lower blood glucose, such as Pramlintide, Metformin, GLP-1 Analogs such as Liraglutide, and nutraceuticals intended to lower blood glucose Beta blockers Oral or injectable glucocorticoids Any other medication that the investigator believes is a contraindication to the subject's participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Closed-Loop Control System<br>Use of an investigational control-to-range automated insulin management (artificial pancreas) system using continuous glucose monitoring (CGM) and subcutaneous insulin pump infusion in individuals with type 1 diabetes in the home environment. | Device: Closed-Loop Control System<br>* This investigational device system included the following components: DiAs - a smart-phone medical platform; Dexcom G4 Platinum CGM system connected to DiAs via CGM receiver and USB-Bluetooth relay hardware; Roche Accu-Chek insulin pump connected to DiAs via wireless Bluetooth; Remote Monitoring Server connected to DiAs via 3G or local Wi-Fi network Modular Closed-Loop Control Algorithm Running on DiAs, which is of Control-to-Range (CTR) class<br>* Other names: Diabetes Assistant (DiAs);|
| Active Comparator: Sensor-Augmented Pump (SAP)<br>Use of a study-assigned commercial continuous glucose monitoring (CGM) system and commercial insulin pump | Device: Sensor-Augmented Pump (SAP)<br>* This commercial device system included the following components: Dexcom G4 Platinum CGM system; Roche Accu-Chek insulin pump<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Spent <70 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values <70 mg/dl during study Main Phase, night only (23:00 to 07:00) | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Spent <70 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values <70 mg/dl during study Main Phase | 2 weeks | 
| Time Spent <70 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values <70 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Time in Range 70-180 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values in range 70-180 mg/dl during study Main Phase | 2 weeks | 
| Time in Range 70-180 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values in range 70-180 mg/dl during study Main Phase, night only (23:00 - 07:00) | 2 weeks | 
| Time in Range 70-180 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values in range 70-180 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Mean Sensor Glucose - Main Phase, Day and Night | Mean CGM sensor glucose during study Main Phase | 2 weeks | 
| Mean Sensor Glucose - Main Phase, Night Only | Mean CGM sensor glucose during study Main Phase, night only (23:00 - 07:00) | 2 weeks | 
| Mean Sensor Glucose - Main Phase, Day Only | Mean CGM sensor glucose during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Glucose Coefficient of Variation - Main Phase, Day and Night | CGM Glucose Coefficient of Variation (CV) during study Main Phase | 2 weeks | 
| Glucose Coefficient of Variation - Main Phase, Night Only | CGM Glucose Coefficient of Variation (CV) during study Main Phase, night only (23:00 - 07:00) | 2 weeks | 
| Glucose Coefficient of Variation - Main Phase, Day Only | CGM Glucose Coefficient of Variation (CV) during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Glucose Standard Deviation - Main Phase, Day and Night | CGM Glucose Standard Deviation (SD) during study Main Phase | 2 weeks | 
| Glucose Standard Deviation - Main Phase, Night Only | CGM Glucose Standard Deviation (SD) during study Main Phase, night only (23:00 - 07:00) | 2 weeks | 
| Glucose Standard Deviation - Main Phase, Day Only | CGM Glucose Standard Deviation (SD) during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Time Spent >180 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values >180 mg/dl during study Main Phase | 2 weeks | 
| Time Spent >180 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values >180 mg/dl during study Main Phase, night only (23:00 to 07:00) | 2 weeks | 
| Time Spent >180 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values >180 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Time Spent <50 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values <50 mg/dl during study Main Phase | 2 weeks | 
| Time Spent <50 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values <50 mg/dl during study Main Phase, night only (23:00 to 07:00) | 2 weeks | 
| Time Spent <50 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values <50 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Time Spent <60 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values <60 mg/dl during study Main Phase | 2 weeks | 
| Time Spent <60 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values <60 mg/dl during study Main Phase, night only (23:00 - 07:00) | 2 weeks | 
| Time Spent <60 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values <60 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| LBGI - Main Phase, Day and Night | Low Blood Glucose Index (LBGI) - Main Phase, Day and Night. The LGBI metric is used to quantify the risk of hypoglycemia. A higher LBGI implies more mild hypoglycemic events or less severe hypoglycemic events. | 2 weeks | 
| LBGI - Main Phase, Night Only | Low Blood Glucose Index (LBGI) - Main Phase, night only (23:00 - 07:00). The LGBI metric is used to quantify the risk of hypoglycemia. A higher LBGI implies more mild hypoglycemic events or less severe hypoglycemic events. | 2 weeks | 
| LBGI - Main Phase, Day Only | Low Blood Glucose Index (LBGI) - Main Phase, day only (07:00 - 23:00). The LGBI metric is used to quantify the risk of hypoglycemia. A higher LBGI implies more mild hypoglycemic events or less severe hypoglycemic events. | 2 weeks | 
| AOC 70 mg/dL - Main Phase, Day and Night | Area Over the Curve (AOC) 70 mg/dL - Main Phase, Day and Night. The hypoglycemia AOC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, a hypoglycemia AOC of 1 mg/dl can denote a glucose of 60 mg/dl for 10% of the time (10 mg/dl below threshold * 10% = 1 mg/dl) or 65 mg/dl for 20% of the time (5 mg/dl below threshold * 20% = 1 mg/dl). Note that it is based on relative (%) rather than absolute time so there is no time element in the resulting units. | 2 weeks | 
| AOC 70 mg/dL - Main Phase, Night Only | Area Over the Curve (AOC) 70 mg/dL - Main Phase, night only (23:00 - 07:00). The hypoglycemia AOC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, a hypoglycemia AOC of 1 mg/dl can denote a glucose of 60 mg/dl for 10% of the time (10 mg/dl below threshold * 10% = 1 mg/dl) or 65 mg/dl for 20% of the time (5 mg/dl below threshold * 20% = 1 mg/dl). Note that it is based on relative (%) rather than absolute time so there is no time element in the resulting units. | 2 weeks | 
| AOC 70 mg/dL - Main Phase, Day Only | Area Over the Curve (AOC) 70 mg/dL - Main Phase, day only (07:00 - 23:00). The hypoglycemia AOC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, a hypoglycemia AOC of 1 mg/dl can denote a glucose of 60 mg/dl for 10% of the time (10 mg/dl below threshold * 10% = 1 mg/dl) or 65 mg/dl for 20% of the time (5 mg/dl below threshold * 20% = 1 mg/dl). Note that it is based on relative (%) rather than absolute time so there is no time element in the resulting units. | 2 weeks | 
| HBGI - Main Phase, Day and Night | High Blood Glucose Index (HBGI) - Main Phase, Day and Night. The HBGI metric is used to quantify the risk of hyperglycemia. A higher HBGI implies more mild hyperglycemic events or less severe hyperglycemic events. | 2 weeks | 
| HBGI - Main Phase, Night Only | High Blood Glucose Index (HBGI) - Main Phase, night only (23:00 - 07:00). The HBGI metric is used to quantify the risk of hyperglycemia. A higher HBGI implies more mild hyperglycemic events or less severe hyperglycemic events. | 2 weeks | 
| HBGI - Main Phase, Day Only | High Blood Glucose Index (HBGI) - Main Phase, day only (07:00 - 23:00). The HBGI metric is used to quantify the risk of hyperglycemia. A higher HBGI implies more mild hyperglycemic events or less severe hyperglycemic events. | 2 weeks | 
| ADRR - Main Phase, Day and Night | Average Daily Risk Range (ADRR) - Main Phase, Day and Night. ADRR is a metric that categorizes risk for hyper and hypoglycemic events. Low risk is scored 0-19, moderate risk is scored 20-40, and high risk is 40 and above. | 2 weeks | 
| AUC 180 mg/dL - Main Phase, Day and Night | Area Under the Curve (AUC) 180 mg/dL - Main Phase, Day and Night. The hyperglycemic AUC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, the hyperglycemic AUC is 28 (mg/dl)*days for Patient A and 56 (mg/dl)*days for Patient B when using 180 as the threshold. But this is artificial because Patient B wore the sensor twice as long. So we similarly scale it relative to the number of readings to reflect a mean rather than a sum. So we say hyperglycemic AUC = 4 mg/dl for both patients. Note that time disappears from the units in the scaled version. It represents the mean value of max(glucose-180, 0). | 2 weeks | 
| AUC 180 mg/dL - Main Phase, Night Only | Area Under the Curve (AUC) 180 mg/dL - Main Phase, night only (23:00 - 07:00). The hyperglycemic AUC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, the hyperglycemic AUC is 28 (mg/dl)*days for Patient A and 56 (mg/dl)*days for Patient B when using 180 as the threshold. But this is artificial because Patient B wore the sensor twice as long. So we similarly scale it relative to the number of readings to reflect a mean rather than a sum. So we say hyperglycemic AUC = 4 mg/dl for both patients. Note that time disappears from the units in the scaled version. It represents the mean value of max(glucose-180, 0). | 2 weeks | 
| AUC 180 mg/dL - Main Phase, Day Only | Area Under the Curve (AUC) 180 mg/dL - Main Phase, day only (07:00 - 23:00). The hyperglycemic AUC is scaled to the number of CGM readings so the time factor cancels out. Technically, the units would be mg/dl, but this might seem unintuitive since it is incremental relative to a threshold. For example, the hyperglycemic AUC is 28 (mg/dl)*days for Patient A and 56 (mg/dl)*days for Patient B when using 180 as the threshold. But this is artificial because Patient B wore the sensor twice as long. So we similarly scale it relative to the number of readings to reflect a mean rather than a sum. So we say hyperglycemic AUC = 4 mg/dl for both patients. Note that time disappears from the units in the scaled version. It represents the mean value of max(glucose-180, 0). | 2 weeks | 
| Time Spent >250 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values >250 mg/dl during study Main Phase | 2 weeks | 
| Time Spent >250 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values >250 mg/dl during study Main Phase, night only (23:00 to 07:00) | 2 weeks | 
| Time Spent >250 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values >250 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 
| Time Spent >300 mg/dL - Main Phase, Day and Night | Percentage of CGM Measured Glucose Values >300 mg/dl during study Main Phase | 2 weeks | 
| Time Spent >300 mg/dL - Main Phase, Night Only | Percentage of CGM Measured Glucose Values >300 mg/dl during study Main Phase, night only (23:00 to 07:00) | 2 weeks | 
| Time Spent >300 mg/dL - Main Phase, Day Only | Percentage of CGM Measured Glucose Values >300 mg/dl during study Main Phase, day only (07:00 - 23:00) | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artificial Pancreas