The Artificial Pancreas in Very Young Children With T1D - Pilot (KidsAP01)
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      The suggested clinical trial is part of the KidsAP project funded by the European
      Commission's Horizon 2020 Framework Programme. The project evaluates the use of the
      Artificial Pancreas (or closed loop systems) in very young children with type 1 diabetes
      (T1D) aged 1 to 7 years. The suggested trial is a feasibility study to pilot the setup of a
      large-scale outcome trial and to address the specific needs of this population. The results
      of the pilot trial will feed into the design of the outcome study.

      In this study the investigators will compare closed loop insulin delivery using standard
      strength insulin to closed loop use with diluted insulin in very young children with T1D.
      Diluted insulin is a standard treatment approach for children with low insulin requirements.
      The investigators hypothesize that diluted insulin will lead to more stable glucose levels by
      reducing inaccuracies accentuated by delivery of minute amounts of insulin (frequently less
      than 0.1U/h [1μl/h with standard strength insulin] in small children compared to 1U/h in
      adults). These inaccuracies may result from pump plunger micro-jumps, tissues pressure
      build-up, and infusion set kinking. This study builds on previous and on-going studies of
      closed loop systems that have been performed in Cambridge in children and adolescents with
      T1D in clinical research facilities and in the home setting.

      The study adopts an open-label, multi-centre, multinational, randomised, two-period crossover
      design contrasting closed loop glucose control using diluted insulin and closed loop using
      standard insulin strength under free-living home conditions. The two intervention periods
      will last 3 weeks each with a 1 to 4 weeks washout period in between. The order of the two
      interventions will be random. A total of up to 30 young children aged 1 to 7 years with T1D
      on insulin pump therapy will be recruited through outpatient diabetes clinics at
      participating clinical centres to allow for 24 completed subjects available for assessment in
      each of the study arms.

      Prior to the use of study devices, participants and parents/guardians will receive
      appropriate training by the research team on the safe use of the study pump and continuous
      glucose monitoring system, and the hybrid closed loop insulin delivery system. Carers at
      nursery or school may also receive training by the study team if required. During the
      intervention periods, subjects and parents/guardians will use the closed loop system for 21
      days under free-living conditions in their home and nursery/school environment without remote
      monitoring or supervision by research staff.

      The primary outcome is time spent in target range between 3.9 and 10.0 mmol/l as recorded by
      CGM. Secondary outcomes are the time spent with glucose levels above and below target, as
      recorded by CGM, and other CGM-based metrics. Safety evaluation comprises the tabulation of
      severe hypoglycaemic episodes.
    

Detailed description: 
      Purpose of clinical trial:

      This is a feasibility study to pilot the outcome study setup and to address the specific
      needs of the studied population by comparing closed loop insulin delivery using standard
      strength insulin (U-100) and diluted insulin. The results will feed into the design of a
      follow up outcome study. The investigators hypothesize that diluted insulin will lead to more
      stable glucose levels by reducing inaccuracies accentuated by delivery of small amounts of
      insulin (frequently less than 0.1U/h [1μl/h with standard strength insulin] in small
      children.

      Study objectives:

      The study objective is to evaluate the safety, efficacy and utility of day-and-night closed
      loop glucose control in young children with type 1 diabetes.

        1. EFFICACY: The objective is to assess the ability of a day-and-night hybrid closed loop
           system using diluted insulin to maintain CGM glucose levels within the target range of
           3.9 to 10mmol/l (70 to 180mg/dl) in comparison with a hybrid closed loop system with
           standard insulin strength in young children with type 1 diabetes.

        2. SAFETY: The objective is to evaluate the safety of day-and-night closed loop using
           diluted insulin versus closed loop with non-diluted insulin in terms of episodes and
           severity of hypoglycaemia, and nature and severity of other adverse events.

        3. UTILITY: The objective is to determine the overall acceptability and duration of use of
           the closed loop system in this population.

      Study Design:

      The pilot study adopts an open-label, multi-centre, multinational, randomised, two-period
      crossover study design contrasting closed loop glucose control using diluted insulin and
      closed loop using standard insulin strength in young children with type 1 diabetes in the
      home setting. Two intervention periods will last 3 weeks each with 1 to 4 weeks washout
      period. The order of the two interventions will be random.

      Participating clinical centres:

        1. Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge,
           UK

        2. Leeds Teaching Hospitals NHS Trust, Leeds, UK

        3. University of Luxembourg, Luxembourg

        4. University of Leipzig, Leipzig, Germany

        5. Medical University of Graz, Graz, Austria

        6. Medical University of Innsbruck, Innsbruck, Austria

        7. Medical University of Vienna, Vienna, Austria

      Sample Size:

      24 participants randomised (2-5 participants per centre), equal proportion of those with
      total daily insulin dose ≤12 U/day and >12 U/day

      Maximum duration of study for a subject: 14 weeks

      Recruitment:

      The subjects will be recruited through paediatric diabetes outpatient clinics at
      participating clinical centres (see above). Enrollment will target up to 30 (2-5 participants
      per centre) to allow for dropouts during run-in (approximately equal proportion of those with
      total daily insulin dose ≤12 U/day and >12 U/day).

      Consent:

      Written informed consent will be obtained from all parents/guardians and written assent from
      older children before any study related activities.

      Baseline Assessment:

      Eligible subjects will undergo a baseline evaluation including a blood sample for the
      measurement of HbA1c. Questionnaires will be completed by parents/guardians.

      Pre-Study Training and Run-in:

      Training sessions on the use of the study CGM and insulin pump will be provided by the
      research team. During a 2-4 week run-in period, subjects will use study CGM and insulin pump.
      For compliance and to assess the ability of the subject to use the study devices safely, at
      least 8 days of CGM data need to be recorded and safe use of study insulin pump demonstrated
      during the last 14 days of run-in period. The CGM data will also be used to assess baseline
      glucose control and may be used for treatment optimization as necessary.

      Competency Assessment:

      Competency on the use of study insulin pump and study CGM will be evaluated using a
      competency assessment tool developed by the research team. Training may be repeated if
      required.

      Randomisation:

      Eligible subjects will be randomised to the use of automated hybrid closed loop glucose
      system with diluted insulin or to closed loop with standard strength insulin for 21 days,
      with a 1-4 week washout period in between the two interventions.

        1. Closed loop with diluted insulin Training on the use of the closed loop system with
           diluted insulin will be provided by the research team. During this 2-4 hour session,
           subjects and parents/guardians will operate the system under the supervision of the
           clinical research team, practicalities around the use of diluted insulin will be
           discussed, and pump settings will be adjusted accordingly. Competency on the use of
           closed loop system will be evaluated. Thereafter, subjects and their parents/guardians
           will continue using the hybrid closed loop system with diluted insulin over 21 days at
           home.

        2. Closed loop with standard insulin strength:

      Identical procedures as described above will be followed including training on the use of the
      closed loop system with standard strength insulin. Subjects will continue using the closed
      loop system with standard strength insulin at home over 21 days.

      End of study assessments:

      Study devices will be downloaded and returned. Participants will resume usual care using
      their pre-study insulin pump. A closed loop experience questionnaire will be completed by
      parents/guardians.

      Procedures for safety monitoring during trial:

      Standard operating procedures for monitoring and reporting of all adverse events will be in
      place, including serious adverse events (SAE) and specific adverse events (AE) such as severe
      hypoglycaemia.

      Criteria for withdrawal of subjects on safety grounds:

      A subject/guardian may terminate participation in the study at any time without necessarily
      giving a reason and without any personal disadvantage. An investigator can stop the
      participation of a subject after consideration of the benefit/risk ratio. Possible reasons
      are:

        -  Serious adverse events

        -  Non-compliance

        -  Serious protocol violation

        -  Decision by the investigator, or the sponsor, that termination is in the subject's best
           medical interest
    

Intervention name(s): FlorenceM
Intervention type(s): Device
Intervention description(s): The automated closed loop system (FlorenceM) will consist of: Next generation sensor augmented Medtronic insulin pump 640G (Medtronic Minimed, CA, USA) incorporating the Medtronic Enlite 3 family real time CGM and glucose suspend feature. An Android smartphone containing the Cambridge model predictive algorithm and communicating wirelessly with the insulin pump using a proprietary translator device.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Type 1 diabetes; Artificial Pancreas; Closed-loop glucose control; Very young children; Continuous subcutaneous insulin infusion; Continuous glucose monitoring