Effect of Closed Loop Glucose Control on Exercise-Associated Hypoglycemia

Study Overview
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Brief Summary
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The purpose of the study is to compare the glycemic control during and following aerobic exercise using either an open or closed-loop insulin delivery system.

Detailed Description
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This is an open-label, single-center, randomized crossover study evaluating the performance of a closed-loop insulin delivery system using a subcutaneous glucose sensor and an external insulin pump and comparing it to an open-loop delivery system during aerobic exercise. Subject participation will be for a maximum of 16 weeks including an outpatient study (up to 6 days) and two inpatient studies (one closed-loop; the other open-loop). The closed- and open-loop visit consists of approximately 67 hours over 4 days and 3 nights.

Official Title
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Effect of Closed Loop Glucose Control on Exercise-Associated Hypoglycemia

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Device: Closed Loop


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 12-30 years of age. Subjects must weigh at least 50 kg to accommodate phlebotomy. Previously diagnosed Type 1 Diabetes Mellitus Diabetes duration at least 1 year. Currently treating their diabetes with an insulin pump. A1C of ≤ 9.0 % at time of enrollment. Willing to have an intravenous (IV) line inserted for frequent blood sampling and infusion of glucose if needed. Willing to wear two (2) subcutaneous glucose sensors and two (2) transmitters simultaneously during closed-loop portion of the study. Be in good general health without other acute or chronic illnesses except treated hypothyroidism or celiac disease and asthma not requiring glucocorticoid use. Able to tolerate a 75-minute exercise period of moderate intensity. Speak and understand English. Subject and parent (if minor) must be able to comprehend and sign the informed consent form and other study documents. Exclusion Criteria: Pregnancy (urine pregnancy test) or lactation, if female. Subject has any major concomitant disease or any physical or psychological disorder within the last five years, which might be considered life threatening, or which might confound the collection or interpretation of the study data. Subject has a cardiac pacemaker or similar device that may be sensitive to radio frequency telemetry. Subject using any of the following medications: glucocorticoids cyclosporine L-asparaginase niacin protease inhibitors anti-psychotics GnRH agonists beta-blockers calcium channel blockers immunosuppressants over-the-counter medications that may effect glucose metabolism. Subject has any of the following conditions insulin allergy severe insulin resistance exercise-induced asthma musculoskeletal problems that may impact ability to complete exercise protocol substance abuse skin ulcers or poor wound healing bleeding disorders chronic infections eating disorders give a history of or are predisposed to major stress any other major organ system disease. Subject has experienced two (2) or more severe hypoglycemic events -seizures/coma requiring assistance in the past six (6) months. Subject has any other condition that in the investigator's opinion warrants exclusion from the study or precludes him/her from completing the protocol. Subjects using dietary supplements within 14 days of study enrollment Subject is currently enrolled in another study.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 30 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: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Closed Loop (CL) Phase<br>Closed Loop (CL) Phase | Device: Closed Loop<br>* Insulin pump controlled by closed loop unit and algorithm<br>|
| No Intervention: Standard of Care (OL) Phase<br>Standard of Care (OL) Phase or Open Loop Phase | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucose (PG) Response to Exercise | PG at start of exercise minus the subsequent PG nadir | Begins at start of exercise, at or after 15:00 on the in-patient visit day randomly assigned each subject for exercise; ends at start of the subsequent meal. Median period: 121 minutes (min), interquartile range (IQR): 15 min, range: 93 to 133 min. | 
| Incidence of Hypoglycemia Immediately Following Exercise | Tally of episodes where either plasma glucose (PG) < 60 mg/dL, or supplemental glucose was administered to prevent imminent PG < 60 mg/dL. Maximum tally of hypoglycemic events within any 30 minute period is 1. | Begins at end of exercise, at or after 16:15 on the in-patient visit day randomly assigned each subject for exercise; ends at 22:00 of same day. Median period: 333 minutes (min), interquartile range (IQR): 28 min, range: 262 to 344 min. | 
| Incidence of Nocturnal Hypoglycemia Following Exercise | Tally of episodes where either plasma glucose (PG) < 60 mg/dL, or supplemental glucose was administered to prevent imminent PG < 60 mg/dL. Maximum tally of hypoglycemic events within any 30 minute period is 1. | Begins at 22:00 on the in-patient visit day randomly assigned each subject for exercise; ends at 6:00 of the subsequent day. Period was 480 minutes (min) for all subjects, both study phases. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Post-prandial Plasma Glucose (PG) | For each subject and study phase, the six peak PG following each of the six meals were determined. The median of these six peaks became the one peak post-prandial PG value representing each subject and study phase. | Union of 6 meal periods (3 per day on study days 2 & 3). A meal period runs from meal start to start of next meal, or 22:00 for 3rd meal of the day. Union of 6 periods median: 1666 minutes (min), interquartile range (IQR): 15 min, range: 1638 to 1680 min. | 
| Nadir Plasma Glucose (PG) Immediately Following Exercise | The PG nadir observed following the start of exercise | Begins at start of exercise, at or after 15:00 on the in-patient visit day randomly assigned each subject for exercise; ends at start of the subsequent meal. Median period: 121 minutes (min), interquartile range (IQR): 15 min, range: 93 to 133 min. | 
| Overnight Nadir Plasma Glucose (PG) | For each subject and study phase, the overnight nadir PG for each of two nights were determined. The mean of these two nadirs became the one nadir overnight PG value representing each subject and study phase. | Union of the two 8-hour overnight periods beginning at 22:00 on in-patient visit days 2 & 3, ending at 6:00 on the subsequent day. The union of the two periods was 960 minutes (min) for all subjects, both study phases. | 
| Percentage of Time Plasma Glucose (PG) is Within the Euglycemic Range. | For each subject and arm, the percentage of the PG curve such that 70 <= PG curve <= 180 mg/dL. Linear interpolations furnished the data between the actual sampled PG to address potential sample influence bias arising from non-uniform sampling intervals. | Begins at 6:00 of in-patient visit day 2 and ends at 6:00 of day 4; 48 hours total. | 
| Percentage of Time Plasma Glucose (PG) is Above the Euglycemic Range. | For each subject and study phase, the percentage of the PG curve > 180 mg/dL. Linear interpolations furnished the data between the actual sampled PG to address potential sample influence bias arising from non-uniform sampling intervals. | Begins at 6:00 of in-patient visit day 2 and ends at 6:00 of day 4; 48 hours total. | 
| Percentage of Time Plasma Glucose (PG) is Below the Euglycemic Range. | For each subject and study phase, the percentage of the PG curve < 70 mg/dL. Linear interpolations furnished the data between the actual sampled PG to address potential sample influence bias arising from non-uniform sampling intervals. | Begins at 6:00 of in-patient visit day 2 and ends at 6:00 of day 4; 48 hours total. |