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.

Inclusion Criteria:

1. Age ≥6 and <19 years

2. Type 1 diabetes as defined by WHO (51) for at least 1 year [WHO definition: 'The
aetiological type named type 1 encompasses the majority of cases with 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.).']

3. Use of an insulin pump for at least 3 months, with good knowledge of insulin
self-adjustment by subject or caregiver as judged by the investigator

4. Using U-100 rapid acting insulin analogues insulin Aspart or Lispro only

5. Willing to perform regular finger-prick blood glucose monitoring, with at least 4
blood glucose measurements per day day

6. Screening HbA1c ≥ 7.5% (58 mmol/mol) and ≤10 % (86mmol/mol) based on analysis from
local laboratory

7. Literate in English

8. Willing to wear glucose sensor

9. Willing to wear closed-loop system at home

10. Willing to follow study specific instructions

11. Willing to upload pump and CGM data at regular intervals

12. Access to WiFi.

13. Lives with someone who is trained to administer intramuscular glucagon and is able to
seek emergency assistance

Exclusion Criteria:

1. Living alone

2. Current use of any closed-loop system

3. Any other 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

4. Untreated coeliac disease, adrenal insufficiency, or untreated thyroid disease

5. Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic
corticosteroids, non-selective beta-blockers and MAO inhibitors etc.

6. Known or suspected allergy to insulin

7. Clinically significant nephropathy (eGFR < 45ml/min) or on dialysis, neuropathy or
active retinopathy (defined as presence of maculopathy or proliferative changes) as
judged by the investigator

8. Recurrent incidents of severe hypoglycaemia (>1 episode) during the previous 6 months
(adolescents: severe hypoglycaemia is defined as an event requiring assistance of
another person to actively administer carbohydrates, glucagon, or take other
corrective actions including episodes of hypoglycaemia severe enough to cause
unconsciousness, seizures or attendance at hospital; children: severe hypoglycaemia is
defined as an event associated with a seizure or loss of consciousness)

9. Recurrent incidents of diabetic ketoacidosis (>1 episode) during previous 6 months

10. Unwilling to avoid regular use of acetaminophen

11. Lack of reliable telephone facility for contact

12. Total daily insulin dose ≥ 2 IU/kg/day

13. Total daily insulin dose < 15 IU/day

14. Pregnancy, planned pregnancy, or breast feeding

15. Severe visual impairment

16. Severe hearing impairment

17. Seizure disorder

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

19. Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located at
places of the body, which potentially are possible to be used for localisation of the
glucose sensor)

20. Illicit drugs abuse

21. Subject is currently abusing prescription drugs

22. Alcohol abuse

23. Use of pramlintide (Symlin), or other non-insulin glucose lowering agents including
sulphonylureas, biguanides, DPP4-Inhibitors, , GLP-1 analogues, SGLT-1/ 2 inhibitors
at time of screening

24. Shift work with working hours between 10pm and 8am

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

26. Eating disorder such as anorexia or bulimia

27. Employed by Medtronic Diabetes or with immediate family members employed by Medtronic
Diabetes