Day and Night Closed-loop in Young People With Type 1 Diabetes
Condition: Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases
Study type: Interventional

Summary: 
      The main study objective is to determine whether 24/7 automated closed-loop glucose control
      combined with low glucose feature will improve glucose control as measured by HbA1c.

      This is an open-label, multi-centre, multi-national, single-period, randomised, parallel
      group design study, involving a 6 month period of home study during which day and night
      glucose levels will be controlled either by a closed-loop system combined with low glucose
      feature (intervention group) or by insulin pump therapy alone (control group).

      It is expected that a total of up to 150 subjects (aiming for 130 randomised subjects) with
      type 1 diabetes will be recruited through paediatric outpatient diabetes clinics of the
      investigation centres. Participants will all be on subcutaneous insulin pump therapy.

      Subjects in the intervention group will have proven competencies both in the use of the study
      insulin pump and the study continuous glucose monitoring (CGM) device, and will receive
      appropriate training in the safe use of closed-loop insulin delivery system and low glucose
      feature. All subjects will have regular contact with the study team during the home study
      phase including 24/7 telephone support. The primary outcome is between group differences in
      HbA1c levels at 6 months post study arm initiation. Secondary outcomes are the time spent in
      the glucose target (3.9 to 10.0mmol/l; 70 to 180mg/dl), 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 of severe hypoglycaemic episodes and diabetic
      ketoacidosis (DKA).
    

Detailed description: 
      -  Purpose of the study: To determine whether 24/7 automated closed-loop glucose control
           will improve glucose control as measured by glycated haemoglobin and reduce the burden
           of hypoglycaemia compared to insulin pump therapy alone.

        -  Study Objectives:

             1. EFFICACY: The objective is to assess efficacy of day and night automated
                closed-loop glucose control in improving glucose control as measured by glycated
                haemoglobin, as compared to insulin pump therapy alone.

             2. SAFETY: The objective is to evaluate the safety of day and night automated
                closed-loop glucose control, in terms of episodes of severe hypoglycaemia and other
                adverse events.

             3. UTILITY: The objective is to determine the frequency and duration of the use of the
                automated closed-loop system.

             4. HUMAN FACTORS: The objective is to assess cognitive, emotional, and behavioural
                characteristics of participating subjects and family members and their response to
                the closed-loop system and clinical trial using validated surveys and focus groups.

             5. HEALTH ECONOMICS: The objective is to perform a cost utility analysis to inform
                reimbursement decision-making.

        -  Study Design: An open-label, multi-centre, randomised, single-period parallel study,
           contrasting day-and-night automated closed-loop glucose control with insulin pump
           therapy alone.

        -  Population: 130 participants randomised (equal proportion of those aged 6 to 12 years
           and 13 to 18 years, a minimum quota of 25% participants with baseline HbA1c >8.5%)

        -  Maximum duration of study for a subject: 8 months

        -  Recruitment: The subjects will be recruited through the pediatric outpatient clinics at
           each center.

        -  Consent: Written consent / assent will be obtained from participants and/or guardians
           according to REC / IRB requirements

        -  Screening Assessments: Eligible participants will undergo a screening evaluation where
           blood samples for full blood count, liver, thyroid function and anti-transglutaminase
           antibodies (with IgA levels if not done within previous 12 months) will be taken.
           Non-hypoglycaemia C-peptide, glucose and HbA1c will also be measured, and a urine
           pregnancy test in females of child-bearing potential will be performed.

      Surveys investigating participants' quality of life, psychosocial and cognitive functioning,
      and response to their current treatment will be distributed.

      Participants will be fitted with a blinded continuous glucose monitoring (CGM) device to
      assess baseline glycaemic control. Instructions on how to safely use, remove and send back
      the device will be provided.

        -  Study Training: Training sessions on the use of study CGM, insulin pump (and closed loop
           system for those randomized to be intervention group) will be provided by the research
           team. Training session on the use of real-time CGM and on how to interpret real-time and
           retrospective stored data will be provided to all subjects / carers using written
           material.

        -  Run-In Period: During a 1-2 week run-in period, subjects will continue using their own
           insulin pump. Data obtained from blinded CGM and pump downloads may be utilised for
           therapy adjustment.

        -  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. Further
           training may be delivered as required.

        -  Randomization: Eligible subjects will be randomised using randomisation software to the
           use of real-time CGM and low glucose feature combined with day and night closed-loop or
           to conventional insulin pump therapy alone.

      A blood sample will be taken for the measurement of HbA1c and a urine pregnancy test in
      females of child-bearing potential. A blood sample for centralised analysis of HbA1c will be
      taken if screening and randomisation are >28 days apart.

        1. Automated day and night closed-loop insulin delivery (intervention arm) combined with
           low glucose feature (interventional arm) - Participants in the closed-loop group will
           receive additional training sessions following randomisation covering the use of the
           study insulin pump and real-time CGM, prior to starting closed-loop insulin delivery.

           Once confident with the use of the study pump and CGM system, participants will receive
           training required for safe and effective use of the closed-loop system approximately 2-4
           weeks after randomisation. During this 2-4 hour session participants will operate the
           system under the supervision of the clinical team. Competency on the use of closed-loop
           system will be evaluated.

           Thereafter, participants are expected to use closed-loop for 6 months without direct
           real-time remote monitoring.

        2. Insulin pump therapy (control arm) - Refresher training on key aspects of insulin pump
           therapy will be provided.

      Subjects will continue using their own insulin pump for 6 months.

        -  3-month and 6 month assessments:

             1. A blood sample will be taken for measurement of HbA1c and a urine pregnancy test in
                females of child-bearing potential.

             2. Validated surveys evaluating the impact of the devices employed on quality of life,
                psychosocial and cognitive functioning, diabetes management and treatment
                satisfaction will be completed.

             3. Participants of both study arms will be fitted with blinded CGM systems at the end
                of each follow up visit. The sensors will be worn at home for up to 14 days and
                will be sent back to the research team.

           6 months only: Subjects/guardians will be invited to join follow-up focus groups to
           gather feedback and reactions to their current treatment (closed-loop or insulin pump),
           the clinical trial, and quality of life changes.

        -  Study Contacts: In between study visits, participants will be contacted by the study
           team (email or phone) once monthly in order to record any adverse events, device
           deficiencies, and changes in insulin settings, other medical conditions and/or
           medication.

      In case of any technical device or problems related to 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.

      --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.

      Subjects will be asked to test and record blood ketones if their finger prick glucose is >
      16.7mmol/l (300mg/dl) upon awakening, >300 for more than 1 hour, or >22.2mmo/l (400mg/dL) at
      any time as part of the safety assessment for DKA.

      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 patients on safety grounds: A subject, parent, or 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 closed-loop intervention
      after consideration of the benefit/risk ratio. Possible reasons are:

        1. Serious adverse events

        2. Significant protocol violation or non-compliance

        3. Failure to satisfy competency assessment

        4. Decision by the investigator, or the sponsor, that termination is in the subject's best
           medical interest

        5. Pregnancy, planned pregnancy, or breast feeding

        6. Allergic reaction to insulin

      Efforts will be made to retain subjects in follow up for the final primary outcome assessment
      even if the intervention is discontinued, unless the investigator believes that it will be
      harmful for the subject to continue in the trial.
    

Intervention name(s): FlorenceM (US) and FlorenceX (UK); Insulin pump therapy
Intervention type(s): Device; Device
Intervention description(s): The automated closed loop system (FlorenceM in US) will consist of:
Next generation sensor augmented Medtronic insulin pump 640G (Medtronic Minimed, CA, USA) incorporating the Medtronic Guardian3 CGM and glucose suspend feature.
The automated closed loop system (FlorenceX in UK) will consist of:
The DANA Diabecare R insulin pump (Sooil Development, Korea) incorporating the Dexcom G6 CGM.
An Android smartphone containing the Cambridge model predictive algorithm and communicating wirelessly with the insulin pump using a proprietary translator device.; Subjects will continue using their own insulin pump for 6 months.
Intervention MeSH terms: Insulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment