Day and Night Closed-loop in Young People With Type 1 Diabetes

• 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.