Fuzzy Logic Automated Insulin Regulation

Purpose of the study: A randomized crossover trial involving up to four clinical sites in the United States and three sites outside the US (Germany, Israel and Slovenia) will compare the efficacy and safety of an AID system with a PID algorithm versus an AID system with a PID algorithm enhanced with a fuzzy logic algorithm.

Study Objectives:

• EFFICACY: The co-primary outcomes are difference in continuous glucose monitoring (CGM)-measured metrics between periods:

• Superiority for percent of time >180 mg/dL (10.0 mmol/L) from 6 AM to 11:59 PM; and
• Non-inferiority of percent of time <54 mg/dL (3.0 mmol/L) during the entire 24-hour period.
• KEY SAFETY OUTCOMES:

• Percentage of sensor glucose readings <54 mg/dL (overall is a co-primary outcomes) and <70 mg/dL (3.0 and 3.9 mmol/L, respectively)
• Diabetic Ketoacidosis (DKA) events
• Severe hypoglycemia events

Study design: Randomized crossover trial with two 12-week crossover periods in automode, preceded by a run-in phase.

Population: A maximum of 124 individuals may be enrolled and start the run-in phase. Approximately 112 are expected to enter the crossover trial, with a goal of at least 100 people completing the trial.

Maximum duration of a study for a subject: Approximately 28-36 weeks.

Recruitment: Subjects will be recruited through the clinical sites.

Consent: Written consent/assent will be obtained for all subjects and/or guardians, in accordance with human subjects and regulatory requirements.

Screening Assessments:

• Informed consent will be signed and eligibility will be assessed
• Medical history and physical examination
• HbA1c measurement
• Urine pregnancy test (if applicable)
• Surveys investigating participants' quality of life, psychosocial and cognitive functioning, and response to their current treatment will be distributed.

Study Training:

Run-In Period: (2-8 weeks)

• Eligible participants will use the study 670G 3.0 HCL pump during the run-in. Participants who were pump users at screening may skip the Pump Run-In period (but must participate in the Pump+CGM Run-In period) per investigator discretion. 670G auto mode users may use the 670G pump in auto mode.

Screening and start of run-in training visits may occur on the same day or separate days, but no more than 14 days apart.

Standardized pump training will be provided to study participants and their diabetes care partners (for participants <18 years old). The study team will assist the participant in study pump infusion site initiation and will start the participant on the study pump. For current pump users, the study pump will be programmed with the participants usual basal rates and pump parameters. The participants personal pump will be removed. Participants may continue to use their personal CGM if applicable.

The pump will be used for at least two weeks during the Pump Run-In, with the option of repeating Pump Run-In for an additional two weeks per investigator discretion. Contact will be made each week with additional contacts as needed. Prior to each contact, participants will be asked to upload device data for study staff to review.

After completion of Pump Run-In, participants will proceed to use the study CGM along with the study 670G HCL pump during the Pump+CGM Run-In period.

• Pump+CGM Run-In (670G 3.0 HCL + Guardian Sensor (3)) All participants must complete a two-week run-in period with the use of the study pump and CGM before being randomized into the crossover trial. During Pump+CGM Run-In, the predictive low glucose suspend feature will be turned on and auto mode will be off (i.e. manual mode). Participants who were 670G auto mode users at screening may use the pump in auto mode.

Standardized device training will be provided to study participants and their diabetes care partners (for participants <18 years old). Personal pumps and CGMs will be removed during the Pump+CGM Run-In period as applicable.

Contact will be made each week with additional contacts as needed. Prior to each contact, participants will be asked to upload device data for study staff to review.

Run-In Assessment Successful completion of Pump Run-In is per investigator discretion. Pump Run-In may be repeated once.

Successful completion of the Pump+CGM Run-In requires CGM data to be collected on at least 80% of the possible time in the prior 14 days of use. An average of at least three blood glucose meter (BGM) tests per day also will be required. If these are not achieved, the Pump+CGM Run-In period may be repeated once.

Randomization into the Crossover Trial

Eligible participants who successfully complete the Pump+CGM Run-In will be randomly assigned to begin with one Automated Insulin Delivery (AID) system during Period 1 and then crossover to the other AID system during Period 2. The two study AID systems (treatments) are:

• 670G 3.0 Hybrid Closed-Loop (HCL) (PID) insulin pump + Guardian Sensor (3) CGM
• 670G 4.0 Advanced Hybrid Closed-Loop (AHCL) (PID + Fuzzy Logic) insulin pump + Guardian Sensor (3) CGM

Home Use of AID System during the Crossover Trial Period 1 (~13 weeks) Participants and their diabetes care partners (for participants <18 years old) will be trained by qualified personnel on the use of the assigned pump and on auto mode feature use including meal announcement, meal bolusing, and exercise.

Training will also be provided in performing specific tasks including the following:

• Confirming pump parameters
• When not to use or rely on auto mode particularly during significant illness or acetaminophen use
• CGM calibration instructions
• Meal bolus procedures
• What to do when exercising while using the system
• How to react to safety/alert notifications
• How to perform fingerstick blood glucose measurements in accordance with the labeling of the study CGM device
• When and how to contact study staff to ask questions during the study

Study staff will discuss the visit and contact schedule with the participant and will make arrangements for follow-up appointments. Participants will be asked to upload data before each contact and at least every two weeks.

After auto mode training has been completed, participants will proceed with home use of the AID system (meaning free-living use at work, home, etc.) during Period 1 with either the 670G 3.0 HCL or 670G 4.0 AHCL pump. The predictive low glucose suspend feature will be on.

The system will initially be used with auto mode deactivated (except for 670G auto mode users at screening who may activate auto mode if using the 670G 3.0 HCL pump) until participants are contacted 6-10 days into Period 1 with instructions to activate auto mode. Participants will be instructed to obtain an overnight fingerstick blood glucose measurement (between 2-3AM) for 2-3 nights following auto mode initiation and if fingerstick blood glucose is <70 mg/dL to treat with carbohydrate. Participants will then continue using the AID system for 12 weeks after auto mode is initialized.

Participants will be expected to use auto mode at all times at home with some exceptions (e.g. times of illness, acetaminophen use).

Participants on the 670G 4.0 AHCL will begin with an auto mode target glucose set point of 120 mg/dL (6.7 mmol/L) that may be lowered to 100 mg/dL (5.6 mmol/L) if participant meets the safety criteria per protocol and investigator discretion.

HbA1c, C-peptide, and glucose levels will be collected for central lab analysis at the beginning of Study Period 1. Human Factors and Diabetes Technology Attitude Surveys will be administered at the end of Study Period 1.

Period 2 (~13 weeks) At the beginning of Period 2, a urine pregnancy test will be completed as applicable. Eligible participants will then use the other AID system during Period 2. The procedures in Period 1 will be repeated in Period 2.

At the end of the 12-weeks of AID use in auto mode at home, the participant will complete a final study visit. That visit may be completed in-person in clinic or in an alternate location such as the participant's home. The study visit may occur remotely via phone or videoconferencing. Certain procedures, such as the measurement of height, weight, vitals, and collection of the central HbA1c sample, may be missed if the visit is not completed in-person. Participants requiring a remote final visit will be transitioned off of the study device during the remote contact and an arrangement will be made between site staff and the participant to return all required study devices either in-person or via mail.

Inclusion criteria

• Type 1 diabetes mellitus (as diagnosed clinically) for at least one year
• Age 14-<30 years at enrollment
• For females, not currently known to be pregnant, be breast-feeding or planning to become pregnant within the study duration.
• Using an insulin pump or multiple daily injections of insulin

• Participant must be able to obtain U-100 rapid acting insulin analogues, Aspart or Lispro, for use during the study (since these are the only insulins approved for the study pump and the study is not supplying insulin)
• MDI users must be on a basal/bolus regimen
• Participants must have a minimum total daily dose (TDD) of at least eight units
• HbA1c from an approved HbA1c point of care analyzer with a value 7.0%-11.0%
• Willingness or ability to do carbohydrate counting
• In the investigator's judgment, able to understand and likely to be adherent to the protocol
• For subjects <18 years old, living with one or more diabetes care partners (eg.g. parent/legal guardian), of whom at least one is committed to participating in study training for emergency procedures for severe hypoglycemia and able to contact the participant in case of an emergency.
• Have adequate internet access and a computer system that meets requirements for uploading data.
• For participants currently using CGM or insulin pump, willingness to discontinue personal CGM and pump when using the study CGM and pumps (note: including implantable CGMs).

Exclusion criteria

Individuals meeting any of the following exclusion criteria at screening will be excluded from study participation:

• Concomitant disease that influences metabolic control or HbA1c interpretation (e.g. anemia, significantly impaired hepatic function, confirmed gastroparesis, renal failure, history of adrenal insufficiency, sickle cell disease, haemoglobinopathy, or has received red blood cell transfusion or erythropoietin within three months prior to time of screening) or other medical condition which, in the Investigator's opinion, may compromise patient safety, affect outcome assessments, or affect the participant's ability to follow the protocol
• Oral or parenteral glucocorticoids taken within 1 month prior to enrollment, or plans to take oral or parenteral glucocorticoids within the planned study duration. Exceptions: Short term oral or parenteral glucocorticoids up to seven days
• Use of antidiabetic agents other than insulin
• Use of other medications, which in the judgment of the investigator would be a contraindication to participation in the study
• One or more episodes of severe hypoglycemia (hypoglycemia requiring treatment by another person) within the previous six months
• Known allergy to medical grade adhesives
• 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 enrollment
• Current eating disorder such as anorexia or bulimia
• Currently abusing illicit drugs, marijuana, prescription drugs, or alcohol
• Visual impairment or hearing loss, which may compromise the participant's ability to perform all study procedures safely, as determined by the investigator
• One or more episodes of diabetic ketoacidosis (DKA) requiring hospitalization within six months prior to screening
• Working night shifts
• Untreated celiac disease, hyperthyroidism, or hypothyroidism
• Clinically significant nephropathy (eGFR <45 mL/min) or on dialysis. Creatinine to determine eGFR must have been obtained as part of usual care within 12 months prior to enrollment (if not available, at time of enrollment, screening can proceed but it must be available prior to randomization)