Outpatient Reduction of Nocturnal Hypoglycemia by Using Predictive Algorithms and Pump Suspension in Children

Study Overview
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Brief Summary
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The purpose of this study is to see whether low blood sugar at night can be reduced by using a system that turns off the insulin pump automatically. The study system includes a continuous glucose monitor (CGM) and an insulin pump. The CGM and pump work with a regular laptop computer. A The system works by (1) measuring the glucose levels under the skin with the CGM, (2) using a computer program on the laptop to predict whether a low blood sugar is likely to occur, and (3) turning off the insulin pump when the computer program predicts that a low blood sugar will occur. We have tested the system in the home environment in individuals with type 1 diabetes age 15 years and older. We have found an indication that the system can decrease the frequency of hypoglycemia. We have not had any serious cases of high blood sugars or other problems. We are now ready to further test the system in the home environment in a younger age group to learn more about its ability to reduce overnight low blood sugar risk. This study has several phases and will take about 3 months for a patient to complete. First, the patient will use the CGM and pump at home for up to 15 days with the help of a parent/guardian. This is done to determine if the patient meets our study criteria to proceed with the next phase of the study. If the patient is eligible to continue in the study, the patient will need to use the full study system for at least 5 nights at home with the help of a parent/guardian. This is done to make sure the patient and parent/guardian are able to use the system correctly. The patient may participate in starting and stopping the system at home, but the parent/guardian is responsible for making sure it is used as instructed. After that, the patient will be asked to use the study system each night for an additional 6 to 8 weeks. The parent/guardian will remain responsible for making sure the system is used as instructed. The study will include about 90 individuals with type 1 diabetes at 3 clinical centers in the United States and Canada. First a study of children 8 to less than 15 years old will be done. Then, a study of children 3 to less than 8 years old will be conducted.

Detailed Description
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Patients who are eligible for the clinical trial initially will use a Veo insulin pump and Enlite sensor at home to verify that the patient is able to use the continuous glucose monitor (CGM) and insert sensors and is eligible to continue in the study. A parent or guardian of the child subject will oversee the actions of the subject and be responsible for the patient's overall participation during the proposed study, including operation of the investigational device system. The first 10 patients 8 to <15 years of age will participate in an Algorithm Assessment Phase of approximately 10 nights of active system use each (for a nominal total of 100 nights of use) to determine if any adjustments to the algorithm parameters are needed and if it is safe to advance to a randomized clinical trial phase with these subjects. If adjustments are needed, the Algorithm Assessment Phase will be repeated, using the same 10 patients if possible. Once the randomized clinical trial phase begins for patients 8 to <15 years of age, approximately 200 nights of randomized system use will be collected and assessed for safety before any patients 3 to <8 years of age may be enrolled in the study. When enrollment does begin for patients 3 to <8 years of age, a second Algorithm Assessment Phase will be conducted with the first 10 patients in that younger age group using the same approach described above for the older subjects. Once the randomized clinical trial phase begins for patients 3 to <8 years of age, a final Data Safety Monitoring Board safety assessment will be performed after approximately the first 200 nights of randomized system use. Patients who enroll in the study after the completion of the Algorithm Assessment Phase for their age group will use the closed-loop system at home for at least 5 days to demonstrate their ability to use the system and submit study data to the Coordinating Center. Patients who successfully demonstrate their ability to use the system at home as described above will be eligible for the randomized trial phase. This phase consists of use of the full system as an outpatient for approximately 42 nights: Each night the blood glucose (BG) level will be checked with the BG meter and used to perform a calibration of the CGM. This calibration must occur no more than 90 minutes prior to activation of the system. NOTE: Subjects will be instructed to calibrate the CGM per manufacturer guidelines. Then the system will be activated, linking the CGM and insulin pump to the computer at the bedside. A randomization schedule on the laptop will be used to determine whether the 'pump shut off' application will be active that night or not. Patients will be blinded as to whether the pump shut off is active when a session is initiated each night. There will not be an alarm if the pump shuts off. The CGM alarm will be set to 60 mg/dL (3.3 mmol/L). When a CGM alarm occurs, the subject will be asked to measure the blood glucose with a BG meter, if he/she is aware of the alarm. Patients will be asked to check blood ketones with the study ketone meter if the subject has a fingerstick BG ≥250 mg/dL (13.9 mmol/L). Patients will be asked to check blood glucose with the study BG meter, blood ketones with the study ketone meter, and urine ketones with a ketone strip each morning prior to breakfast and enter the results using the controller software interface. The patient will be instructed to contact the study physician if the blood glucose or ketone readings are out of an expected range. Patients will be asked to record all overnight carbohydrate intake using the controller software interface. Patients will be asked to perform periodic CGM data uploads using the controller software interface. Upon completion of the study, patients as well as study clinicians will be asked to complete a human factors usability questionnaire regarding use of the study system.

Official Title
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Outpatient Reduction of Nocturnal Hypoglycemia by Using Predictive Algorithms and Pump Suspension in Children

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Device: Pump suspension algorithm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of type 1 diabetes and using daily insulin therapy for at least one year and an insulin infusion pump for at least 6 months Age 3 to <15 years HbA1c <=8.5% Availability of internet access for periodic upload of study data Exclusion Criteria: Diabetic ketoacidosis in the past 3 months Hypoglycemic seizure or loss of consciousness in past 6 months History of seizure disorder (except for hypoglycemic seizures) Cystic fibrosis Current use of oral/inhaled glucocorticoids, beta-blockers or other medications, which in the judgment of the investigator would be a contraindication to participation in the study History of ongoing renal disease (other than microalbuminuria), or liver disease (Creatinine is > 1.5 mg/dL (132 µmol/L)) Medical or psychiatric condition that in the judgment of the investigator might interfere with the completion of the protocol such as: Inpatient psychiatric treatment in the past 6 months Uncontrolled adrenal disorder Abuse of alcohol Pregnancy Liver disease as defined by an Alanine Aminotransferase Test (ALT) greater than 3 times the upper limit of normal

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 14 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pump suspension algorithm<br>The pump suspension algorithm will be running actively on the study laptop during the night and suspend the pump if the algorithm predicts hypoglycemia. | Device: Pump suspension algorithm<br>* The study laptop will communicate to the pump causing a suspension based on output from the algorithm which predicts hypoglycemia.<br>|
| No Intervention: Standard of Care<br>The control algorithm will run passively and not suspend the patient's pump. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Time Spent in Hypoglycemia (<70 mg/dl, 3.9 mmol/L) Overnight on Intervention Nights Versus Control Nights, Normalized to an 8-hour Period. | Each night is categorized as to whether hypoglycemia occurred. Hypoglycemia is defined as the occurrence of one or more CGM glucose values ≤70 mg/dL (3.9 mmol/L). The time period for outcome assessment each night will be from the time the system is activated in the evening until the time it is deactivated in the morning. The percentage of hypoglycemic nights (CGM glucose value ≤70 mg/dL (3.9 mmol/L)) will be tabulated separately with versus without the closed-loop control system in use. We considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Nights With 1 or More Sensor Glucose Values <70 mg/dL (<3.9 mmol/L) | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use. | 
| Percentage of Nights With 1 or More Sensor Glucose Values <50 mg/dL (<2.8 mmol/L) | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Mean Sensor Glucose Overnight | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Percentage of Time Overnight Sensor Glucose Values 71 to 180 mg/dL (3.9 to 10.0 mmol/L), Normalized to an 8-hour Period. | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Percentage of Overnight Time Spent With CGM Value >250 mg/dL (13.9 mmol/L), Normalized to an 8-hour Period. | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Mean Morning Blood Glucose | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Percentage of Mornings With Blood Glucose >250 mg/dL (>13.9 mmol/L) | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Morning Blood Ketones >=1.0 mmol/L | Please note we considered nights with at least 4 hours of sensor glucose data as a valid night toward the 42 night overall goal and thus our final analyses had a slightly higher number of nights than expected. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 
| Percent of Mornings With Urine Ketones >/= 15 mg/dl | Urine ketones measured each morning with Ketostix. | Overnight from system activation to deactivation in the morning upon awakening for 42 nights of system use | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 Diabetes, Hypoglycemia, Continuous Glucose Monitoring, Pump Suspension