The Artificial Pancreas in Very Young Children With T1D
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 with additional funding by JDRF. The project
      evaluates the use of the Artificial Pancreas (or closed loop system) in very young children
      with type 1 diabetes (T1D) aged 1 to 7 years. The suggested trial is an outcome study to
      determine whether 24/7 automated closed loop glucose control will improve glucose control as
      measured by time in range compared to sensor augmented pump therapy. In the extension phase,
      the purpose is to evaluate the effect of long-term home use of 24/7 automated hybrid closed
      loop insulin delivery on glucose control (UK sites only).

      The study adopts an open-label, multi-centre, multi-national, randomised, two period,
      cross-over design study, comparing two 16-week periods during which glucose levels will be
      controlled either by a closed loop system (intervention period) or by sensor augmented pump
      therapy (control period).

      Participants will complete a 2 to 4 week run-in period, followed by two treatment periods
      that will last 16 weeks each, with a 1 to 4 week washout period in between. The order of the
      two treatments will be random. A total of up to 80 young children aged 1 to 7 years with T1D
      on insulin pump therapy (aiming for 72 randomised subjects) will be recruited through
      paediatric outpatient diabetes clinics of the investigation centres.

      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 device, 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 closed loop study arm, subjects and parents/guardians will use the closed loop
      system for 16 weeks under free-living conditions in their home and nursery/school environment
      without remote monitoring or supervision by research staff.

      During the control study arm, subjects and parents/guardians will use sensor augmented pump
      therapy for 16 weeks under free-living conditions in their home and nursery/school
      environment. All subjects will have regular contact with the study team during the home study
      phase including 24/7 telephone support.

      The primary endpoint 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 assessment of the
      frequency and severity of hypoglycaemic episodes and diabetic ketoacidosis (DKA).

      During the extension phase, participants will have follow-up contacts every 3 months.

      The primary endpoint is time spent in target range, between 3.9 and 10.0 mmol/l as recorded
      by CGM, over 18 months from the end of the primary phase, as compared to sensor augmented
      pump therapy during the primary phase. Secondary outcomes as well as safety and utility will
      be assessed as per primary phase.
    

Detailed description: 
      Purpose of clinical trial:

      To determine whether 24/7 automated hybrid closed loop will improve glucose control as
      measured by time within the target range compared with sensor augmented pump therapy in very
      young children with T1D.

      Study objectives:

      The study objective is to evaluate the safety, efficacy and utility of automated hybrid
      closed loop glucose control in very young children with type 1 diabetes.

        1. EFFICACY: The objective is to assess the ability of a hybrid closed loop system to
           maintain CGM glucose levels within the target range of 3.9 to 10 mmol/l (70 to 180
           mg/dl) in comparison with sensor augmented pump therapy in very young children with type
           1 diabetes.

        2. SAFETY: The objective is to evaluate the safety of closed loop glucose control compared
           with sensor augmented pump therapy in terms of episodes and severity of hypoglycaemia,
           frequency of diabetic ketoacidosis (DKA) and nature and severity of other adverse
           events.

        3. UTILITY: The objective is to determine the acceptability and duration of use of the
           closed loop system in this population.

        4. HUMAN FACTORS: The objective is to assess emotional and behavioural characteristics of
           participants and parents/guardians and their response to the closed loop system and
           clinical trial using validated surveys and semi-structured qualitative interviews.

        5. HEALTH ECONOMICS: The objective is to perform a cost utility analysis to inform
           reimbursement decision-making.

      Participating clinical centres:

        1. Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge,
           UK

        2. Leeds Teaching Hospitals NHS Trust, Leeds, UK

        3. DECCP, Centre Hospitalier de Luxembourg, Grand Duché de 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:

      72 participants randomised (8-12 participants per centre). At the primary phase final visit,
      participants (UK sites only) on sensor-augmented pump therapy as their standard clinical care
      will be invited to participate in an extension phase of closed loop therapy for a further 18
      months.

      Maximum duration of study for a subject: 11 months (primary phase). 29 months for
      participants (UK sites only) opting to participate in 18-month extension phase.

      Recruitment:

      The subjects will be recruited through paediatric diabetes outpatient clinics at
      participating clinical centres (see above). Enrolment will target up to 80 (aiming for 8-12
      participants per centre) to allow for dropouts during run-in.

      Participants (UK sites only) completing the primary phase, who are on sensor-augmented pump
      therapy as their standard clinical care, will be invited to participate in the extension
      phase.

      Consent:

      Written informed consent will be obtained from all parents/guardians and written assent from
      older children before any study related activities.

      Additional written consent will be obtained for the extension phase from all
      parents/guardians.

      Baseline Assessment:

      Eligible subjects will undergo a baseline assessment 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 using randomisation software to the initial use of
      automated hybrid closed loop glucose system or to sensor augmented pump therapy for 16 weeks
      with a 1 to 4 week washout period before crossing over to the other study arm.

      Automated day and night closed loop insulin delivery (intervention arm)

      Participants in the closed loop arm and their caregivers will receive an additional training
      session covering the use of the closed loop system provided by the research team prior to
      starting closed loop insulin delivery. During this 1-2 hour session, parents/guardians will
      operate the system under the supervision of the clinical research team. Competency on the use
      of closed loop system will be evaluated. Thereafter, subjects and their parents/guardians
      will use the hybrid closed loop system for 16 weeks at home.

      Crossover Assessment:

      At the end of the first study arm, a blood sample for the measurement of HbA1c will be taken
      and weight and height will be measured. Validated surveys evaluating the impact of the
      devices employed on quality of life, psychosocial function, diabetes management and treatment
      satisfaction will be completed.

      Parents/guardians will be invited to be interviewed to gather feedback on and reactions to
      their current treatment, the clinical trial, and quality of life changes.

      Sensor augmented pump therapy (control arm):

      Participants in the sensor augmented pump therapy arm and their caregivers will receive
      refresher training on key aspects of insulin pump therapy and CGM use.

      Subjects and their parents/guardians will continue using sensor augmented pump therapy for 16
      weeks at home.

      Study contacts:

      Participants will be contacted 24h after starting each study arm to ensure there are no
      concerns regarding the study devices. In between study visits, participants will be contacted
      by the study team (email/phone) once monthly and 3-monthly in the extension phase, in order
      to record any adverse events, device deficiencies, and changes in insulin settings, other
      medical conditions and/or medication.

      In case of any problems related to the technical device or diabetes management such as hypo-
      or hyperglycaemia, subjects will be able to contact a 24-hour telephone helpline to the local
      research team at any time. The local research team will have access to central 24 hour advice
      on technical issues.

      End of study assessments (primary phase):

      A blood sample will be taken for measurement of HbA1c at the end of the study. Height and
      weight will be recorded. Study devices will be downloaded and returned. Participants will
      resume usual care using their pre-study insulin pump. Validated surveys evaluating the impact
      of the devices employed on quality of life, psychosocial function and diabetes management and
      treatment satisfaction will be completed.

      Parents/guardians will be invited to participate in a sleep sub-study prior to the final
      visit (UK & Luxembourg only).

      Parents/guardians will be invited to be interviewed to gather feedback on and reactions to
      their current treatment, the clinical trial, and quality of life changes.

      Extension Phase (UK sites only):

      Follow up contacts will be conducted 3-monthly, in line with routine clinic visits, including
      recording of adverse events, medical history, insulin requirements and HbA1c.

      After 18 months from the end of the primary phase, parents/guardians will complete validated
      questionnaires evaluating the impact of the technology on quality of life, diabetes
      management, sleep quality and fear of hypoglycaemia. Height and weight will be measured. A
      blood sample will be taken for measurement of HbA1c at the end of the extension phase

      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), serious adverse device effects (SADE) and
      specific adverse events (AE) such as severe hypoglycaemia.

      A data safety and monitoring board (DSMB) will be informed of all serious adverse events and
      any unanticipated serious adverse device effects that occur during the study and will review
      compiled adverse event data at periodic intervals.

      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

        -  Allergic reaction to insulin
    

Intervention name(s): CamAPS FX; Sensor augmented therapy
Intervention type(s): Device; Other
Intervention description(s): CamAPS FX closed loop system comprises:
Dana insulin pump (Diabecare, Sooil, Seoul, South Korea)
Dexcom G6 real-time CGM sensor (Dexcom, Northridge, CA, USA)
An Android smartphone hosting CamAPS FX app with the Cambridge model predictive control algorithm and communicating wirelessly with the insulin pump and glucose sensor
Cloud upload system to monitor CGM/insulin data; Study insulin pump and study CGM.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Device: CamAPS FX
The automated closed loop system (CamAPS FX) will consist of:
Dana RS insulin pump (Diabecare, Sooil, Seoul, South Korea)
Dexcom G6 real-time CGM sensor (Dexcom, Northridge, CA, USA)
An Android smartphone hosting CamAPS FX app with the Cambridge model predictive control algorithm and communicating wirelessly with the insulin pump and glucose sensor
Cloud upload system to monitor CGM/insulin data.
Masking: None (Open Label)
Primary purpose: Treatment