Reduction of Nocturnal Hypoglycemia and Hyperglycemia in the Home Using Predictive Algorithms
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1; Hypoglycemia; Hyperglycemia
Study type: Interventional
Phase: Phase 2

Summary: 
      Objective: to gain experience with in-home use of a modified algorithm that will dose insulin
      to minimize projected hyperglycemia overnight in addition to suspending the pump if
      hypoglycemia is projected overnight and to obtain feasibility, safety, and initial efficacy
      data.

      Study Design: randomized controlled trial, with randomization on a night level within
      subject.

      Major Eligibility Criteria: clinical diagnosis of type 1 diabetes, daily insulin therapy for
      at least one year and an insulin infusion pump for at least 6 months; 15.0 to <46.0 years of
      age; HbA1c < 10.0%; no DKA in last 6 months; no hypoglycemic seizure or loss of consciousness
      in last 6 months; Living with a significant other or family member ("companion") committed to
      participating in all study activities, and being present and available to provide assistance
      when the system is being used at night.

      Sample Size: 30 subjects.

      Study Duration and Visit Schedule: duration approximately 3 months, with preliminary run-in
      activities followed by up to 90 days spent in clinical trial phase of study; clinic visits at
      enrollment, following CGM and system assessment run-in phases, at start of clinical trial
      phase, at 21-day point of clinical trial phase, and after 42 nights of successful system use.

      Major Efficacy Outcomes:

        -  Primary: time in range (70-180 mg/dl, 3.9-10.0 mmol/L) overnight.

        -  Secondary: time spent in hypoglycemia (≤70 mg/dl, 3.9 mmol/L) and time spent in
           hyperglycemia (>180 mg/dl, 10.0 mmol/L) overnight.

      Major Safety Outcomes: CGM measures of hypo- and hyperglycemia, including morning blood
      glucose and mean overnight sensor glucose; adverse events including severe hypoglycemia and
      diabetic ketoacidosis.
    

Detailed description: 
      Subjects who are eligible for the clinical trial initially will use a Veo insulin pump and
      Enlite 2 CGM sensor at home for a minimum of 6 days/week over a 2-week period to verify that
      the subject is able to use the CGM and insert sensors.

      The first 10 subjects enrolled will participate in a 2-day overnight hotel-based pilot,
      collecting a total of 20 nights of data and experience with the system in a transitional
      hotel setting. The DSMB will review safety data from the 20 night hotel-based pilot study and
      make recommendations regarding proceeding to the at-home portion of the study.

      Following DSMB review and approval of the safety data from the hotel study, the first 10
      subjects will participate in an Algorithm Assessment Phase of approximately 10 nights of
      Predictive Low Glucose Suspend (PLGS) + Hyper Minimization system use each (for a nominal
      total of 100 nights of use at home) to determine if any adjustments to the algorithm
      parameters are needed and if it is safe to advance to the randomized clinical trial phase. If
      adjustments are needed, the Algorithm Assessment Phase will be repeated, using the same 10
      subjects if possible. Once the randomized clinical trial phase begins, approximately 200
      nights of randomized system use will be collected and assessed for safety by the DSMB before
      proceeding.

      New subjects who enroll in the study after the completion of the Algorithm Assessment Phase
      will use the PLGS+Hyper Minimization closed-loop system at home for at least 5 days to
      demonstrate their ability to use the system and submit study data to the Coordinating Center.

      Subjects who successfully demonstrate their ability to use the system at home as described
      above will be eligible for the randomized trial phase. This phase consists of use of the full
      system in the home for approximately 42 nights:

        -  Each night the blood glucose level will be checked with the BG meter and used to perform
           a calibration of the CGM. This calibration must occur no more than 90 minutes prior to
           activation of the system. NOTE: Subjects will be instructed to calibrate the CGM per
           manufacturer guidelines.

        -  Then the system will be activated, linking the CGM and insulin pump to the computer at
           the bedside.

        -  A randomization schedule on the laptop will be used to determine whether the system will
           run in PLGS+Hyper Minimization mode or PLGS-only.

        -  Subjects will be blinded as to whether the system is running in PLGS+Hyper Minimization
           mode or PLGS-only.

        -  There will not be an alarm if the pump shuts off or if automated insulin dosing occurs.
           The CGM alarm will be set to 60 mg/dL (3.3 mmol/L). When a CGM alarm occurs, the subject
           will be asked to measure the blood glucose with a BG meter, if he/she is aware of the
           alarm.

        -  The time period for outcome assessment each night will be from the time the system is
           activated until it is turned off in the morning.

        -  Pump shut off, when it occurs, will be for up to 120 minutes in a 150-minute period, and
           no more than 180 minutes for the entire night. Multiple instances of pump suspension can
           occur if there are recurrent predictions of hypoglycemia during the night.

        -  Small correction boluses of insulin will be delivered when the system predicts that
           hyperglycemia above a pre-set threshold will occur, with insulin-on-board constraints
           and cumulative delivery limits to minimize the likelihood of excessive insulin delivery.

        -  Subjects will be asked to check blood glucose with the study BG meter each morning prior
           to breakfast and enter the results using the controller software interface. The subject
           will be instructed to contact the study physician if the morning blood glucose value is
           <60 mg/dl (3.3 mmol/L) or >300 mg/dl (16.7 mmol/L). Monitoring processes detailed in
           section 3.11 will ensure that the subject can be contacted if these values are not
           reported as required or are out of range.

        -  Subjects will be asked to record all overnight carbohydrate intake using the controller
           software interface.

        -  Subjects will be asked to perform periodic CGM data uploads using the controller
           software interface. Monitoring processes will ensure that the subject can be contacted
           if these uploads do not occur as required, or if review of an upload reveals any
           extreme, prolonged episodes of hypoglycemia or hyperglycemia, or elevated morning blood
           glucose values.

      Upon completion of the study, subjects as well as study clinicians will be asked to complete
      a human factors usability questionnaire regarding use of the study system.
    

Intervention name(s): Hyperglycemia Minimization Algorithm
Intervention type(s): Device
Intervention description(s): The hyperglycemia minimization algorithm will be running actively on the study laptop during the night and dose insulin if the algorithm predicts hyperglycemia. If hypoglycemia is predicted, the system will suspend the pump.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Type 1 Diabetes; Hypoglycemia; Hyperglycemia; Artificial Pancreas