The suggested clinical trial is part of the KidsAP project funded by the European Commission's Horizon 2020 Framework Programme and JDRF. It evaluates the use of the Artificial Pancreas (closed loop system) in very young children with type 1 diabetes (T1D) aged 1-7 years. This outcome study aims to determine whether 24/7 automated closed loop glucose control improves time in range compared to sensor augmented pump therapy. An extension phase will evaluate the effect of long-term home use of the 24/7 automated hybrid closed loop insulin delivery system on glucose control (UK sites only).

The study employs an open-label, multi-centre, multi-national, randomized, two-period, crossover design. Participants undergo a 2-4 week run-in period, followed by two 16-week treatment periods (one for each therapy) separated by a 1-4 week washout. The order of treatments is randomized. Up to 80 young children (with a target of 72 randomized subjects) on insulin pump therapy will be recruited from paediatric outpatient diabetes clinics.

Before using the study devices, participants and their parents/guardians receive training on the safe use of the study pump, continuous glucose monitoring (CGM) device, and hybrid closed loop system. Nursery or school carers may also be trained if needed. During the closed loop arm, subjects use the system for 16 weeks under free-living conditions at home and in nursery/school without remote monitoring. In the control arm, subjects use sensor augmented pump therapy for 16 weeks under similar conditions, with regular contact and 24/7 telephone support from the study team.

The primary endpoint is the time spent in the target glucose range (3.9-10.0 mmol/l) as recorded by CGM. Secondary outcomes include the time spent with glucose levels above and below target and other CGM metrics. Safety assessments include the frequency and severity of hypoglycaemic episodes and diabetic ketoacidosis (DKA). In the extension phase, participants have follow-up contacts every 3 months, with the primary endpoint measured over 18 months from the end of the primary phase and compared to sensor augmented pump therapy during that phase. Secondary outcomes, safety, and utility will be assessed similarly.

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

Inclusion Criteria:

1. Age between 1 and 7 years (inclusive) (Luxembourg and Austria)
2. Age between 2 and 7 years (inclusive) (Germany and UK)
3. Type 1 diabetes as defined by WHO for at least 6 months [WHO definition: 'The aetiological type named type 1 encompasses the majority of cases which are primarily due to beta-cell destruction, and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those with beta-cell destruction for which neither an aetiology nor a pathogenesis is known (idiopathic). It does not include those forms of beta-cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects, etc.).']
4. Insulin pump user (with or without continuous glucose monitoring or flash glucose monitoring system) for at least 3 months, with subject/carer good knowledge of insulin self-adjustment as judged by the investigator
5. On sensor-augmented pump as standard clinical care (extension phase only)
6. Treated with rapid or ultra-rapid acting insulin analogue
7. Subject/carer is willing to perform regular finger-prick blood glucose monitoring, with at least 2 blood glucose measurements taken every day
8. Screening HbA1c ≤ 11% (97mmol/mol) on analysis from local laboratory
9. Willing to wear glucose sensor
10. Willing to wear closed loop system 24/7 during intervention arm
11. The subject/carer is willing to follow study specific instructions
12. The subject/carer is willing to upload pump and CGM data at regular intervals

Exclusion Criteria:

1. Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator

2. Untreated coeliac disease or thyroid disease based on local investigations prior to study enrolment

3. Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic corticosteroids

4. Use of closed loop insulin delivery within the past 2 months

5. Known or suspected allergy to insulin

6. Carer's lack of reliable telephone facility for contact

7. Subject/carer's severe visual impairment

8. Subject/carer's severe hearing impairment

9. Medically documented allergy towards the adhesive (glue) of plasters or subject is unable to tolerate tape adhesive in the area of sensor placement

10. Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located in parts of the body which could potentially be used for localisation of the glucose sensor)

11. Sickle cell disease, haemoglobinopathy; or has received red blood cell transfusion or erythropoietin within 3 months prior to time of screening

12. Plan to receive red blood cell transfusion or erythropoietin over the course of study participation

13. Subject/carer not proficient in English (UK, Germany, Austria, Luxembourg) or German (Germany, Austria, Luxembourg) or French (Luxembourg)

    Additional exclusion criteria - Germany only

14. Known microvascular diabetes complications (retinopathy, renal disease, neuropathy)

15. Eating disorders

16. Psychiatric diseases of the parents that would possibly interfere with the ability to comply to study procedures

17. Major needle phobia that would complicate to wear pump catheter and sensor

18. Congenital malformations that would interfere with diabetes treatment (e.g. congenital heart malformations, lung diseases, renal malformations)

19. Growth hormone deficiency

20. Combined Hypopituitarism

21. Down Syndrome (high risk for comorbidity with coeliac disease, autoimmune thyroiditis)

22. Cancer under treatment

23. Current participation in other interventional clinical trials

Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication. To gain access, data requestors will need to sign a data access agreement.

Fully anonymised data may be shared with third parties (EU or non-EU based) for the purposes of advancing management and treatment of diabetes.

Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication.

Study protocol, statistical analysis plan and fully anonymised individual participant data that underlie the results reported in the manuscript will be available 6 months following publication and ending 36 months following manuscript publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose, to achieve aims in the approved proposal. Proposals should be directed to rh347@cam.ac.uk and may be submitted up to 36 months following article publication.

Over both 16-week study periods (total 32 weeks).

Severe hypoglycaemia was defined as per ISPAD guidance: If the event requires assistance of another person due to altered consciousness to actively administer carbohydrate, glucagon, or other resuscitative actions. This means that the subject is impaired cognitively to the point that he/she is unable to treat him- or herself, is unable to verbalize his or her needs, is incoherent, disoriented, and/or combative, or experiences seizure or coma.