Home Testing of Day and Night Closed Loop With Pump Suspend Feature

Purpose of the study:

To determine whether day and night automated closed loop glucose control combined with pump
suspend feature will improve glucose control as measured by glycated haemoglobin and reduce
the burden of hypoglycaemia compared to sensor augmented insulin pump therapy.

Study objectives:

1. EFFICACY: The objective is to assess efficacy of day and night automated closed loop
glucose control combined with pump suspend feature in maintaining glucose levels within
the target range from 3.9 to 10.0mmol/l (70 to 180mg/dl) based on subcutaneous
continuous glucose monitoring (CGM), as compared to sensor augmented insulin pump
therapy.

2. SAFETY: The objective is to evaluate the safety of day and night automated closed loop
glucose control combined with pump suspend feature, 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. PSYCHOSOCIAL: Subjects' and family members' perception in terms of life-style change,
diabetes management and fear of hypoglycaemia will be assessed using validated
questionnaires and semi-structured qualitative interviews. Cognitive functions will be
assessed using validated computerized cognitive tests.

Study design:

An open-label, multi-centre, multi-national, randomised, single-period, parallel group study,
contrasting day and night automated closed loop glucose control combined with pump suspend
feature with sensor augmented insulin pump therapy

Population:

84 participants randomised (42 youth and 42 adults). Each centre will aim to recruit between
05 and 20 participants.

Maximum duration of study for a subject :

18 weeks

Recruitment:

The subjects will be recruited through the paediatric and adult diabetes outpatient clinics
at each centre.

Consent:

Written consent/assent will be obtained from participants and/or guardians according to
REC/IRB requirements.

Screening assessment:

Eligible participants will undergo a screening evaluation where blood samples for full blood
count, renal, liver, thyroid function and anti-transglutaminase antibodies with IgA levels
will be taken (if not done in the previous 3 months). Random C-peptide, glucose and HbA1c
will also be measured, and a urine pregnancy test in females of child-bearing potential.

Questionnaires investigating participants' quality of life, psychosocial functioning and
response to their current treatment will be distributed. Cognitive assessment will be made
using validated computerized cognitive tests.

Study Training:

Training sessions on the use of study CGM, insulin pump (and closed loop system for those
randomised to the 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 4 week run-in period, subjects will use study CGM and insulin pump. The research
team will contact subject once weekly during the run-in period, and subjects will also be
able to contact the research team for support and treatment optimisation as necessary. For
compliance and to assess the ability of the subject to use the CGM and study pump safely, at
least 12 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.

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.

Randomisation:

Eligible subjects will be randomised using randomisation software to the use of real-time CGM
and pump suspend feature combined with day and night closed loop or to sensor augmented
insulin pump therapy.

1. Automated day and night closed loop insulin delivery (intervention arm) combined with
pump suspend feature (interventional arm):

At the start, a blood sample will be taken for the measurement of HbA1c and a urine
pregnancy test in females of child-bearing potential.

A subset of participants will be interviewed to enable their historical diabetes
management practices, everyday work and family lives, and their initial expectations of
using closed loop technology to be captured and explored in-depth.

Subjects will be admitted to the clinical facility on Day 1. Training on the use of
closed loop and pump suspend feature will be provided by the research team. During the
next 2-4 hours patient will operate the system under the supervision of the clinical
team. Competency on the use of closed loop system will be evaluated. Subjects will use
closed loop and pump suspend feature for 12 weeks.

2. Sensor augmented insulin pump therapy (control arm):

A blood sample will be taken for the measurement of HbA1c and a urine pregnancy test in
females of child-bearing potential. Subjects will use sensor augmented insulin pump therapy
without pump suspend feature for 12 weeks.

End of study assessments:

- A blood sample will be taken for measurement of HbA1c.

- Validated questionnaires evaluating the impact of the devices employed on life change,
diabetes management will be completed.

- Cognitive assessment will be made using validated computerized cognitive tests.

- Follow-up interviews will be undertaken with the subset of participants/family members
at the end of the closed loop intervention.

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 or urine ketones if their finger prick
glucose is above 14.0mmol/l (250mg/dl) in the morning on waking, as part of the safety
assessment for hyperglycaemia.

- 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 participation of a subject 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

7. Technical grounds (e.g. subject relocates)

Inclusion Criteria:

1. The subject is at least 6 years or older [with equal proportion of youth (6 to 21
years) and adults (22 years and older)]

2. The subject has type 1 diabetes, as defined by WHO for at least 1 year or is confirmed
C-peptide negative

3. The subject will have been an insulin pump user for at least 3 months, with good
knowledge of insulin self-adjustment as judged by the investigator

4. The subject is treated with one of the rapid acting insulin analogues (insulin Aspart,
Lispro or Glulisine)

5. The subject is willing to perform regular capillary blood glucose monitoring, with at
least 4 blood glucose measurements taken every day

6. Screening HbA1c ≥ 7.5% (58.5mmol/mol) and ≤ 10 % (86mmol/mol) based on analysis from
local laboratory or equivalent [with equal proportion of subjects above and below
HbA1c 8.5% (69mmol/mol)]

7. The subject is literate in English

8. The subject is willing to wear glucose sensor

9. The subject is willing to wear closed loop system at home

10. The subject is willing to follow study specific instructions

11. The subject is willing to upload pump and CGM data at regular intervals

12. The subject is willing to restrict alcohol consumption to ≤ 2 units per day throughout
the study period

13. Female subjects of child bearing age should be on effective contraception and must
have a negative urine-HCG pregnancy test at screening.

14. The subject lives with someone who is trained to administer intramuscular glucagon and
is able to seek emergency assistance.

15. The subject has access to WIFi at home.

Exclusion Criteria:

1. Non-type 1 diabetes mellitus including those secondary to chronic disease

2. Subject using real-time CGM on regular basis in preceding 3 months

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 or thyroid disease or subject is being treated for
hypothyroidism at time of screening

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. Subjects with 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. Adults: one or more episodes of severe hypoglycaemia as defined by American Diabetes
Association (33) in preceding 6 months; Youth: recurrent incidents of severe
hypoglycaemia during the previous 6 months (Adults and 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. Random C-peptide > 100pmol/l with concomitant plasma glucose >4 mmol/l (72 mg/dl)

10. 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. Significantly reduced hypoglycaemia awareness in subjects 18 year and older (screening
Gold score > 4)

18. Subjects using implanted internal pace-maker

19. Patients with medically documented allergy towards the adhesive (glue) of plasters or
Subject is unable to tolerate tape adhesive in the area of sensor placement

20. 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)

21. Subject is currently abusing illicit drugs

22. Subject is currently abusing prescription drugs

23. Subject is currently abusing alcohol

24. Subject is using pramlintide (Symlin) at time of screening

25. Subject has elective surgery planned that requires general anaesthesia during the
course of the study

26. Subject is a shift worker with working hours between 10pm and 8am

27. Subject has a sickle cell disease, haemoglobinopathy; or has received red blood cell
transfusion or erythropoietin within 3 months prior to time of screening

28. Subject plans to receive red blood cell transfusion or erythropoietin over the course
of study participation

29. Subject diagnosed with current eating disorder such as anorexia or bulimia

30. Subject plans to use significant quantity of herbal preparations (use of over the
counter herbal preparation for 30 consecutive days or longer period during the study)
or significant quantity of vitamin supplements (four times the recommended daily
allowance used for 30 consecutive days or longer period during the study) during the
course of their participation in the study