The Artificial Pancreas in Very Young Children With T1D - Pilot (KidsAP01)

Purpose of clinical trial:

This is a feasibility study to pilot the outcome study setup and to address the specific needs of the studied population by comparing closed loop insulin delivery using standard strength insulin (U-100) and diluted insulin. The results will feed into the design of a follow up outcome study. The investigators hypothesize that diluted insulin will lead to more stable glucose levels by reducing inaccuracies accentuated by delivery of small amounts of insulin (frequently less than 0.1U/h [1μl/h with standard strength insulin] in small children.

Study objectives:

The study objective is to evaluate the safety, efficacy and utility of day-and-night closed loop glucose control in young children with type 1 diabetes.

• EFFICACY: The objective is to assess the ability of a day-and-night hybrid closed loop system using diluted insulin to maintain CGM glucose levels within the target range of 3.9 to 10mmol/l (70 to 180mg/dl) in comparison with a hybrid closed loop system with standard insulin strength in young children with type 1 diabetes.
• SAFETY: The objective is to evaluate the safety of day-and-night closed loop using diluted insulin versus closed loop with non-diluted insulin in terms of episodes and severity of hypoglycaemia, and nature and severity of other adverse events.
• UTILITY: The objective is to determine the overall acceptability and duration of use of the closed loop system in this population.

Study Design:

The pilot study adopts an open-label, multi-centre, multinational, randomised, two-period crossover study design contrasting closed loop glucose control using diluted insulin and closed loop using standard insulin strength in young children with type 1 diabetes in the home setting. Two intervention periods will last 3 weeks each with 1 to 4 weeks washout period. The order of the two interventions will be random.

Participating clinical centres:

• Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
• Leeds Teaching Hospitals NHS Trust, Leeds, UK
• University of Luxembourg, Luxembourg
• University of Leipzig, Leipzig, Germany
• Medical University of Graz, Graz, Austria
• Medical University of Innsbruck, Innsbruck, Austria
• Medical University of Vienna, Vienna, Austria

Sample Size:

24 participants randomised (2-5 participants per centre), equal proportion of those with total daily insulin dose ≤12 U/day and >12 U/day

Maximum duration of study for a subject: 14 weeks

Recruitment:

The subjects will be recruited through paediatric diabetes outpatient clinics at participating clinical centres (see above). Enrollment will target up to 30 (2-5 participants per centre) to allow for dropouts during run-in (approximately equal proportion of those with total daily insulin dose ≤12 U/day and >12 U/day).

Consent:

Written informed consent will be obtained from all parents/guardians and written assent from older children before any study related activities.

Baseline Assessment:

Eligible subjects will undergo a baseline evaluation 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 to the use of automated hybrid closed loop glucose system with diluted insulin or to closed loop with standard strength insulin for 21 days, with a 1-4 week washout period in between the two interventions.

• Closed loop with diluted insulin Training on the use of the closed loop system with diluted insulin will be provided by the research team. During this 2-4 hour session, subjects and parents/guardians will operate the system under the supervision of the clinical research team, practicalities around the use of diluted insulin will be discussed, and pump settings will be adjusted accordingly. Competency on the use of closed loop system will be evaluated. Thereafter, subjects and their parents/guardians will continue using the hybrid closed loop system with diluted insulin over 21 days at home.
• Closed loop with standard insulin strength:

Identical procedures as described above will be followed including training on the use of the closed loop system with standard strength insulin. Subjects will continue using the closed loop system with standard strength insulin at home over 21 days.

End of study assessments:

Study devices will be downloaded and returned. Participants will resume usual care using their pre-study insulin pump. A closed loop experience questionnaire will be completed by parents/guardians.

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) and specific adverse events (AE) such as severe hypoglycaemia.

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

Inclusion criteria

• Age between 1 and 7 years of age (inclusive)
• Type 1 diabetes as defined by WHO for at least 6 months
• 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
• Treated with rapid acting insulin analogue insulin Aspart (Novo Nordisk, Bagsvaerd, Denmark)
• Subject/carer is willing to perform regular finger-prick blood glucose monitoring, with at least 4 blood glucose measurements taken every day
• Screening HbA1c ≤ 11% (97mmol/mol)
• Willing to wear glucose sensor
• Willing to wear closed loop system 24/7
• The subject/carer is willing to follow study specific instructions
• The subject/carer is willing to upload pump and CGM data at regular intervals

Exclusion criteria

• 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
• Untreated coeliac disease or thyroid disease based on local investigations prior to study enrolment
• Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic corticosteroids
• Known or suspected allergy to insulin
• Recurrent incidents of severe hypoglycaemia (>2 episodes) during the previous 6 months [severe hypoglycaemia is defined as an event associated with a seizure or loss of consciousness]
• Unwilling to avoid regular use of acetaminophen
• Carer's lack of reliable telephone facility for contact
• Total daily insulin dose ≥ 2 IU/kg/day
• Subject/carer's severe visual impairment
• Subject/carer's severe hearing impairment
• Medically documented allergy towards the adhesive (glue) of plasters or subject is unable to tolerate tape adhesive in the area of sensor placement
• 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)
• Sickle cell disease, haemoglobinopathy; or has received red blood cell transfusion or erythropoietin within 3 months prior to time of screening
• Plan to receive red blood cell transfusion or erythropoietin over the course of study participation
• Subject/carer not proficient in English (UK) or German (Germany, Austria, Luxembourg) or French (Luxembourg)