Prevention of Hypoglycemia After Exercise Using Closed Loop System in Children and Adolescents With Type 1 Diabetes

Study Overview
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Brief Summary
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The Study will compare treatment with Closed Loop (CL) system - DreaMed MD-AID to the standard treatment without computer algorithm decisions - SAP therapy in 20 children and adolescents with Type 1 Diabetes (T1D) during and after afternoon physical activity. The aims of the study are: to demonstrate that the use of DreaMed MD-AID is safe during physical activity to investigate the risk of hypoglycemia among children and adolescents with T1D after afternoon exercise during closed-loop control.

Detailed Description
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This is investigator initiated, single-center, open-label, crossover, randomized, interventional, in-hospital pediatric study, performed at the University Children's Hospital, University Medical Center Ljubljana. Study duration will be about 4 weeks per subject, 6 month overall. The study will compare Continuous Glucose Monitoring (CGM) based time in hypoglycemia in an intervention arm (Glucose control using DreaMed MD-AID) to a control arm (Glucose control using SAP). Each arm includes two exercise days with 1 week in-between. Subjects will be randomly assigned to participate first in the intervention arm (10 subjects) or first in the control arm (10 subjects). At the end of the first period patients will be asked to participate in another, i.e. the other arm with at least one week between arms. Subjects will be instructed to consume a similar diet and avoid caffeine, alcohol, and physical activity in the 48 hours before the exercise day visit. The start of the run-in period can be scheduled as a separate visit, but not more than 2 days after screening. All subjects will attend the clinic on six occasions: Visit 1: Screening and sensor/pump education, detailed physical examination will be performed, all subject will have to meet inclusion/exclusion criteria. Visit 2: Baseline assessment of the DreaMed MD-AID profile, subjects will perform resting electrocardiography (ECG) and determination of the maximal oxygen consumption rate (VO2max) on a cycle ergometer Ganshorn LF8.5G™ and Schiller software, with BG measurements before, at the end of the exercise and 2 hours after exercise. Subjects will be instructed to refrain from physical activity for 48 hours prior to visits 3 - 6. Visit 3: 24 hours DreaMed MD-AID or SAP with afternoon exercise (in the time between 16:30 and 19:30): an i.v. catheter will be inserted in the antecubital or cephalic vein (for plasma BG and emergency). Cycle ergometer will be adjusted for each subject (work rate, seat height,..), they will be instructed to pedal at steady rate of 50-60 rotations per minute (RPM).The subjects will cycle for 40 minutes at 55% Vo2max load (starting work rate set to 30 watts (W) with linear loading to reach 55% VO2max on 5:00 minute exercise time) - the aim of this session is to induce delayed hypoglycemia. Visit 4: 24 hours DreaMed MD-AID or SAP with afternoon exercise (in the time between 16:30 and 19:30): an i.v. catheter will be inserted in the antecubital or cephalic vein (for plasma BG and emergency). Cycle ergometer will be adjusted for each subject (work rate, seat height,..), they will be instructed to pedal at steady rate of 50-60 rotations per minute (RPM). The subjects will cycle for 40minutes - high intensity interval training (2 - 6 sprints of 20 seconds at 80% VO2max with interval of 6 minutes low-moderate activity (55% VO2max (total of  40 minutes) between the sprint. The aim of this session is to imitate children's physical activity (bursts of intensive physical activity interspersed with varying intervals of activity of low and moderate intensity. Visit 5&6: Same as visits 3 and 4, cross over from DreaMed MD-AID to SAP or vice versa. During the exercise, a continuous ECG will be recorded and inhaled O2 and exhaled Carbon Dioxide (CO2) will be measured. BG and lactate will be taken during the exercise visits: at the beginning of the exercise, after every 15 min exercise session, and every half an hour for the next 2 hours thereafter. All hypoglycemia will be confirmed with SBGM: glucose values <3.3 (60 mg/dl) mmol/l if symptomatic, and all hypoglycemia with self blood glucose monitoring (SBGM) values <2.8 mmol/l (50 mg/dl) (regardless of symptoms) will be treated with rescue carbohydrates as per standard in-hospital procedure (15 g sugar per 10 kg of body weight (BW), re-evaluate and repeat if necessary in 15-30 minutes). New infusion set and two continuous glucose sensors (one for back-up) will be inserted in the subcutaneous tissue of the arm and then calibrated the day before each visit from 3 to 6. Schedule for all exercise days will be similar: 12:00 hospital admission 13:00 lunch 13:30 to 16:00 rest 16:00 afternoon snack 16:30 to 19:30 exercise protocol 19:45 dinner 21:00 to 7:30 next day: bed time 8:00 breakfast. 13:00 lunch and end of study Subjects will have standardized and similar meals on all exercise days (lunch at 13:00, afternoon snack at 16:00, dinner at 19:45, and breakfast at 8:00 the next day), based on the weight, with calculated carbohydrates and calories: 1 gram of carbohydrates per kilogram, the content of the meal according to the recommendation: comprising of 50% carbohydrate, 20% protein, and 30% fat, of which no more than 10% will be saturated fat. During the exercise the SAP group will turn off the insulin pump and lower their basal insulin for 20% for the next 4 hours after the exercise.

Official Title
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Prevention of Hypoglycemia After Exercise Using DreaMed Substance Administration Device in Children and Adolescents With Type 1 Diabetes (The PHYSI-DREAM Study)

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Device: DreaMed Substance Administration Device
* Device: Sensor Augmented Pump (SAP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed by a parent/legal guardian and informed assent signed by the study participant prior study entry. Diagnosed with T1D, as defined by the American Diabetes Association and World Health Organization (ADA/WHO) for at least 1 year prior to study enrolment. Documented evidence should exist within the patient history of T1D. Age between 10 and 17 years (inclusive) at the time of enrolment. Treatment with insulin pump therapy for at least 3 months. HbA1C value ≤ 9% based on analysis from the local laboratory at the time of enrolment (A1C testing must follow National Glycohemoglobin Standardization Program (NGSP) standards). Willing to follow all study instructions (child and parent should be evaluated as one) Availability for the entire study duration and follow-up visits Willing to perform daily self-monitoring of blood glucose (SMBG) and required sensor calibrations If also present celiac/Hashimoto disease, the disease has to be adequately treated as determined by the investigator BMI above 5th centile and below 95th centile for age, respectively. Exclusion Criteria: Concomitant diseases that influence metabolic control (e.g. anemia, significantly impaired hepatic function, renal failure, history of adrenal insufficiency) or other medical conditions, which in the investigator's opinion, may compromise patient safety; Note: Adequately treated thyroid disease and celiac disease do not exclude subjects from enrollment. Significant co-morbidity that, in the opinion of the investigators would preclude participation in the study (e.g. current treatment for cancer, mental disorder) Any concomitant oral or parenteral glucocorticoids therapy within 1 month prior to screening, or planning to take oral or parenteral glucocorticoids during the study. (Exceptions: Short term oral glucocorticoids up to 7 days, inhaled steroids). Any concomitant therapy with antidiabetic agents or other medications, which could be a contraindication to participation in the study by the judgment of the investigator. Participation in another study of a medical device or drug that could affect glucose measurements or glucose management or Receipt of any investigational medical product within 1 month prior to screening (Visit 1). Female subject of child-bearing potential who is pregnant, breast-feeding, or planning to become pregnant during the study. Subject that has known hypoglycemic unawareness or recurrent severe hypoglycemic events with seizure and/or coma (more than two episodes) within 6 months prior to screening. History of one or more episodes of Diabetic Ketoacidosis (DKA) requiring hospitalization within a month prior to the screening. Current or recent history of alcohol or drug abuse. Visual impairment or hearing loss, which in the investigator's opinion, may compromise patient ability to perform study procedures safely (child and parent should be evaluated as a unit).

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 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: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glucose control using DreaMed MD-AID<br>In this group the subjects use a closed loop system (DreaMed Substance Administration Device) that combines glucose monitoring system (S.C wired sensor, named Sof® Sensor™ or Enlite® Sensor™), which provides real-time interstitial glucose values, with a modern insulin pump (MiniMed® Paradigm® Veo™, Medtronic) and computer algorithm, which directs insulin delivery in response to glucose sensor data. | Device: DreaMed Substance Administration Device<br>* 2 exercise days under DreaMed MD-AID control with afternoon exercise (in the time between 16:30 and 19:30). New infusion set and two continuous glucose sensors (one for back-up) will be inserted in the subcutaneous tissue of the arm and then calibrated the day before each visit from 3 to 6. The continuous glucose sensor continuously will measure interstitial glucose levels and these values will be sent by the Minilink™ via wireless, low-powered, radio frequency to the Paradigm Veo every 5 minutes for up to 6 days. The DreaMed MD-AID uses a vendor-supplied and self-developed (communication module) communication application programming interface (API) in order to retrieve glucose / insulin data from the Paradigm Veo and set insulin treatment according to the algorithm decision.<br>|
| Active Comparator: Glucose control using SAP<br>In this group the subjects use a standard treatment (Sensor Augmented Pump), characterised by glucose monitoring system (S.C wired sensor, named Sof® Sensor™ or Enlite® Sensor™) which provides real-time interstitial glucose values and a modern insulin pump (MiniMed® Paradigm® Veo™, Medtronic) without computer algorithm decisions. | Device: Sensor Augmented Pump (SAP)<br>* 2 exercise days under Sensor Augmented Pump with afternoon exercise (in the time between 16:30 and 19:30). New infusion set and two continuous glucose sensors (one for back-up) will be inserted in the subcutaneous tissue of the arm and then calibrated the day before each visit from 3 to 6. The continuous glucose sensor continuously will measure interstitial glucose levels and these values will be sent by the Minilink™ via wireless, low-powered, radio frequency to the Paradigm Veo every 5 minutes for up to 6 days. During the exercise the group will turn off the insulin pump and lower their basal insulin for 20% for the next 4 hours after the exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to evaluate the safety and efficacy of blood glucose control using the DreaMed MD-AID in children and adolescents with T1D during and after planned physical activity, in a controlled in-hospital environment. | Primary endpoint is significant between-group difference (intervention DreaMed MD-AID versus control SAP) in time of hypoglycemia below 3.3 mmol/l (60 mg/dl) during the afternoon exercise and the afternoon/night after (till 13:00 next day) based on sensor glucose readings with a minimum duration of 20 minutes. | After all patients completed their 30 days of study treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to evaluate the physiologic responses and risk of hypoglycemia among children and adolescents with T1D after afternoon exercise during closed-loop control in a controlled in-hospital environment | Time of hypoglycemia below 3.9 mmol/l (70 mg/dl) based on sensor glucose readings. Time of hyperglycemia above 13.9 mmol/l (250 mg/dl) based on sensor glucose readings. Time of glucose values within 3.9 - 10 mmol/l (70-180 mg/dl). | After all patients completed their 30 days of study treatment. |