Fuzzy Logic Automated Insulin Regulation
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): MedtronicMinimed 670G 3.0 hybrid closed loop system; Medtronic Minimed 670G 4.0 AHCL with Guardian Sensor (3) continuous glucose monitoring sensor.
Intervention type(s): Device; Device
Intervention description(s): The components of the intervention are the insulin pump with insulin delivery algorithm (PID).; The components of the intervention are the insulin pump with insulin delivery algorithm (PID + Fuzzy Logic) and Guardian Sensor (3).
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized crossover trial with two 12-week crossover periods in auto mode preceded by a run-in phase.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hybrid closed loop; Closed loop; Artificial pancreas