Fuzzy Logic Automated Insulin Regulation
Fuzzy Logic Automated Insulin Regulation
Adolescents and young adults with type 1 diabetes often have a difficult time achieving good
 glucose control, which is so important in reducing the risk for diabetes complications.
 Despite the use of multiple daily injections or insulin pumps and glucose sensors, there is
 still a need for many individuals to further improve glucose levels without causing low blood
 glucose levels (hypoglycemia) or adding to the daily burden of living with diabetes. Today an
 insulin pump can receive glucose readings from a continuous glucose monitor and adjust the
 insulin delivery in an attempt to keep glucose levels in a more optimal range. These systems
 are called hybrid closed loop (HCL). This means that much of the insulin delivery is
 automated, yet the patient still interacts regularly with the system, particularly to help
 determine the insulin dose to deliver to cover a meal. Results of early studies using HCL
 systems in adolescents and adults with type 1 diabetes are encouraging.

 The objective of this study is to compare the efficacy and safety of the automated insulin
 delivery (AID) system with proportional integral-derivative (PID) algorithm (Minimed 670G 3.0
 HCL) to an AID system with combined PID and Fuzzy Logic Algorithm (Minimed 670G 4.0 Advanced
 Hybrid Closed-Loop (AHCL)). The trial will test the hypothesis that the Minimed AHCL can
 reduce daytime hyperglycemia, currently the biggest challenge for AID systems, without
 increasing hypoglycemia.

 Up to 124 adolescents and young adults (ages 14-<30) will be recruited to test each system
 for three months in a randomized crossover trial. Investigators will compare how effective
 each hybrid closed loop system is at preventing high blood glucose readings during the day.
 The investigators will also evaluate the safety of each system and how participants adjust to
 the daily use of the technology.
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:

 1. 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.

 2. 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:

 1. Type 1 diabetes mellitus (as diagnosed clinically) for at least one year

 2. Age 14-<30 years at enrollment

 3. For females, not currently known to be pregnant, be breast-feeding or planning to
 become pregnant within the study duration.

 4. Using an insulin pump or multiple daily injections of insulin

 1. 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)

 2. MDI users must be on a basal/bolus regimen

 3. Participants must have a minimum total daily dose (TDD) of at least eight units

 5. HbA1c from an approved HbA1c point of care analyzer with a value 7.0%-11.0%

 6. Willingness or ability to do carbohydrate counting

 7. In the investigator's judgment, able to understand and likely to be adherent to the
 protocol

 8. 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.

 9. Have adequate internet access and a computer system that meets requirements for
 uploading data.

 10. 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:

 1. 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

 2. 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

 3. Use of antidiabetic agents other than insulin

 4. Use of other medications, which in the judgment of the investigator would be a
 contraindication to participation in the study

 5. One or more episodes of severe hypoglycemia (hypoglycemia requiring treatment by
 another person) within the previous six months

 6. Known allergy to medical grade adhesives

 7. 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

 8. Current eating disorder such as anorexia or bulimia

 9. Currently abusing illicit drugs, marijuana, prescription drugs, or alcohol

 10. Visual impairment or hearing loss, which may compromise the participant's ability to
 perform all study procedures safely, as determined by the investigator

 11. One or more episodes of diabetic ketoacidosis (DKA) requiring hospitalization within
 six months prior to screening

 12. Working night shifts

 13. Untreated celiac disease, hyperthyroidism, or hypothyroidism

 14. 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)