Adapting Diabetes Treatment Expert Systems to Patient in Type 1 Diabetes

Four cohorts of about 25 participants each (expected retention 20 per cohort). Each cohort will continue for \~7 months. Following recruitment, screening, and a run-in period of SAM, participants will be randomized into one of two groups: escalation vs. de-escalation of devices and function. Each treatment modality (SAM - Sensor-Augmented Mode, PF - Personalized Feedback, DSS - Decision Support Systems) will continue for about 8 weeks, with the last 4 weeks used to assess glucose variability (GV) from CGM data.

• Personalized Feedback (Device): Provides tailored information to the user about what glycemic risk they may be facing as well as how glycemic control and system use looked in the past week. Treatment decision and therapy changes are entirely left to the decision of the user.
• Decision Support System (Device): CGM-based system that includes Personalized Feedback (PF) and further assists with treatment recommendations for common metabolic challenges
• Sensor Augmented Mode (Device): A mode in Diabetes Assistant (DiAs) that combines Diabetes Assistant, Insulin pump or Multiple Daily Injections, CGM, ketone meters, and glycemic treatment guidelines together to manage diabetes.

Primary outcomes

• Glycemic Outcomes [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Glucose Variability (GV) as measured by CGM-based Coefficient of Variation (CV), as recommended by the International Consensus on Use of Continuous Glucose Monitoring.

Secondary outcomes

• Percent Time in Clinical Hypoglycemia [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Percentage of time blood glucose was below 54mg/dL as per CGM
• Percent Time Below Recommended Threshold [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Percentage of time blood glucose was below 70mg/dL as per CGM
• Percent Time in Target Range [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Percentage of time blood glucose was 70mg/dL and 180mg/dL as per CGM
• Percent Time Above Range [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Percentage of time blood glucose was above 180mg/dL as per CGM
• Percent Time Above 250 mg/dL [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: Percentage of time blood glucose was above 250mg/dL as per CGM
• Average Glycemia [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: average of CGM values
• Low Blood Glucose Index [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: The low blood glucose index (LBGI) is based on a nonlinear transformation of blood glucose values that corrects for the asymmetry of the glucose scale. This transformation maps glucose values into a risk space (minimum risk = 0), where higher values correspond to higher risk. Values <1 suggest low risk of hypoglycemia.
• High Blood Glucose Index [Assessed over the last 4 weeks (Weeks 4 - 8), for each intervention]: The high blood glucose index (HBGI) is based on a nonlinear transformation of blood glucose values that corrects for the asymmetry of the glucose scale. This transformation maps glucose values into a risk space (minimum risk = 0), where higher values correspond to higher risk. Values below 10 suggest low to moderate risk.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age 18 years and older
* Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year and using insulin for at least one year
* HbA1c 6.0-11.0%, inclusive
* Demonstration of proper mental status and cognition for the study
* If on a non-insulin hyperglycemic therapy, stability on that therapy for the prior 3 months and willingness not to alter the therapy for the study duration.
* For females, not currently known to be pregnant
* If female and sexually active, must agree to use a highly effective form of contraception to prevent pregnancy while a participant in the study. A negative serum or 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. Also, subjects who during the study develop and express the intention to become pregnant within the timespan of the study will be discontinued.
* Subjects must have Internet access and a computer system that meets the requirements for uploading the study equipment and ability to participate in video conferencing.
* Investigator has confidence that the subject can successfully operate all study devices and is capable of adhering to the protocol

Exclusion Criteria:

* NPH (neutral protamine hagedorn) insulin
* Use of any medication that at the discretion of the investigator is deemed to interfere with the trial.
* Current treatment of a primary seizure disorder
* Coronary artery disease or heart failure, unless written clearance is received from a cardiologist.
* Hemophilia or any other bleeding disorder
* A known medical condition, which in the opinion of the investigator or designee, would put the participant or study at risk such as the following examples:

  * Inpatient psychiatric treatment in the past 6 months
  * Presence of a known adrenal disorder
  * Abnormal liver function test results (Transaminase >3 times the upper limit of normal)
  * Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2).
  * Active gastroparesis requiring medical therapy
  * Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L).
  * Abuse of alcohol or recreational drugs
  * Infectious process not anticipated to be resolved prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis, deep tissue infection).
  * Uncontrolled arterial hypertension (Resting diastolic blood pressure >100 mmHg and/or systolic blood pressure >180 mmHg).
  * Uncontrolled microvascular complications such as current active proliferative diabetic retinopathy defined as proliferative retinopathy requiring treatment (e.g. laser therapy or VEGF inhibitor injections) in the past 12 months.
* 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.
* Not familiar with smart phone technology
* Current use of the following drugs and supplements:

  * Oral steroids
  * Any other medication that the investigator believes is a contraindication to the subject's participation
* Participation in another pharmaceutical or device trial at the time of enrollment or during the study.

Participant flow

Outcome results

• Glycemic Outcomes (Primary), Mean, Percent of coefficient of variation: Escalation 36.3 +/- 4.0; De-escalation 35.7 +/- 6.7
• Percent Time in Clinical Hypoglycemia (Secondary), Mean, Percent of time: Escalation 0.5 +/- 0.8; De-escalation 0.7 +/- 0.7
• Percent Time Below Recommended Threshold (Secondary), Mean, Percentage of time: Escalation 2.5 +/- 2.4; De-escalation 3.5 +/- 3.3
• Percent Time in Target Range (Secondary), Mean, Percentage of time: Escalation 53.9 +/- 16.9; De-escalation 60.1 +/- 16.9
• Percent Time Above Range (Secondary), Mean, Percent of time: Escalation 43.6 +/- 18.2; De-escalation 36.4 +/- 18.8
• Percent Time Above 250 mg/dL (Secondary), Mean, Percentage of time: Escalation 16.6 +/- 12.6; De-escalation 11.4 +/- 11.0
• Average Glycemia (Secondary), Mean, mg/dl: Escalation 179.1 +/- 32.3; De-escalation 164.9 +/- 31.2
• Low Blood Glucose Index (Secondary), Mean, index: Escalation 0.7 +/- 0.5; De-escalation 0.9 +/- 0.7
• High Blood Glucose Index (Secondary), Mean, index: Escalation 10.6 +/- 5.7; De-escalation 8.3 +/- 5.0

Adverse events

Time frame: 7 months

Serious adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-10-05)
• Informed Consent Form (PDF, 2022-12-01)

• Marc Breton, PhD, Principal investigator, University of Virginia Center for Diabetes Technology

NIH grants: R01DK051562