FASter Insulin in Closed-loop Technology in Children
FASter Insulin in Closed-loop Technology in Children
The main objective of this study is to compare 24/7 hybrid closed-loop insulin delivery under
 free living conditions applying faster insulin aspart (FiAsp) to 24/7 hybrid closed-loop
 insulin delivery applying standard insulin aspart in very young children with type 1
 diabetes.

 The closed-loop system consists of three components: the continuous glucose monitor (CGM),
 the insulin pump and a smartphone Application, or App, that translates, in real-time, sensor
 glucose levels received from the glucose monitoring device and calculates the amount of
 insulin to be delivered by the coupled insulin pump.

 This is a double-blind, multi-centre, randomised, crossover design study, involving a run-in
 period followed by two 8-week study periods during which glucose levels will be controlled by
 a hybrid closed-loop system using either standard insulin aspart or faster insulin aspart in
 random order.

 Participants aged 2-6 years with type 1 diabetes on insulin pump therapy will be recruited
 through paediatric diabetes outpatient clinics at participating clinical centres. Enrolment
 will target up to 30 children (aiming for 6-14 participants per centre) to allow for dropouts
 during run-in.

 Prior to the use of study devices, participants and parents/guardians will receive
 appropriate training by the research team on the safe use of the study pump and CGM device,
 and the hybrid closed-loop insulin delivery system. Parents/guardians at nursey/school may
 also receive training by the study team if required. Participants will have regular contact
 with the study team during the study including 24/7 telephone support. Parents/guardians will
 be asked to complete validated questionnaires at the start and end of the study to assess
 quality of life measures including sleep.

 The primary outcome is the between group difference in time spent in target range between 3.9
 and 10.0 mmol/l as recorded by CGM during the study. Secondary outcomes are time spent with
 glucose levels above and below target, as recorded by CGM, and other CGM-based metrics.
 Safety evaluation comprises assessment of the frequency and severity of hypoglycaemic
 episodes and diabetic ketoacidosis (DKA).
Purpose of clinical trial:

 To compare hybrid closed-loop applying faster insulin aspart to hybrid closed-loop applying
 standard insulin aspart over 8 weeks.

 Study objectives:

 The study objective is to compare hybrid closed-loop glucose control using faster insulin
 aspart with hybrid closed-loop control using standard insulin aspart in very young children
 with type 1 diabetes.

 1. EFFICACY: The objective is to assess the ability of a hybrid closed-loop system applying
 faster insulin aspart to maintain CGM glucose levels within the target range from 3.9 to
 10.0 mmol/l, in comparison to a hybrid closed-loop system applying standard insulin
 aspart in very young children with type 1 diabetes.

 2. SAFETY: The objective is to evaluate the safety of closed-loop glucose control using
 faster insulin aspart compared to standard insulin aspart 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.

 4. HUMAN FACTORS: The objective is to assess emotional and behavioural characteristics of
 parents/guardians and their response to the closed-loop system and clinical trial using
 validated surveys.

 Participating clinical centres:

 1. Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge

 2. John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford

 3. Nottingham Children's Hospital, Nottingham

 Sample Size:

 24 children randomised (6-14 participants per centre).

 Maximum duration of study for a subject:

 6 months

 Recruitment:

 Participants will be recruited through the paediatric diabetes outpatient clinics at
 participating clinical centres (see above). Enrolment will target up to 30 participants
 (aiming for 6-14 participants per centre), to allow for dropouts during run-in.

 Consent:

 Written informed consent will be obtained from all parents/guardians.

 Screening and baseline Assessment:

 Eligible participants will undergo a baseline assessment including a blood sample for the
 measurement of HbA1c. Height and weight will be recorded. Validated 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. Participants and parents/guardians will use the study CGM and insulin pump
 during a 2-4 week run-in period. For compliance and to assess the ability of the participant
 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 the run-in period. The CGM data
 will also be used to assess baseline glucose control and may be used for treatment
 optimisation as necessary.

 Competency Assessment:

 Competency on the use of study pump and study CGM will be evaluated by the research team.
 Training may be repeated if required.

 Randomisation:

 Eligible participants will be randomised using randomisation software to the initial use of
 faster insulin aspart with the hybrid closed-loop system or to standard insulin aspart with
 the hybrid closed-loop system for 8 weeks before crossing over to the other treatment arm.

 Hybrid closed-loop system training:

 Parents/guardians of participants in both groups 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 if required. During this session, parents/guardians will operate
 the system under the supervision of the clinical research team. Competency on the use of the
 closed-loop system will be evaluated. Thereafter, participants and their parents/guardians
 will use the hybrid closed-loop system for 4 months at home with either faster insulin aspart
 or standard insulin aspart first.

 1. Faster insulin aspart with hybrid closed-loop:

 Participants and their parents/guardians will use the hybrid closed-loop system with
 faster insulin aspart for 8 weeks at home. The participant, parents/guardians and the
 research team will be blinded to the intervention.

 Crossover assessment:

 At the end of the first study arm, validated questionnaires will be completed by the
 parents/guardians.

 2. Standard insulin aspart with hybrid closed-loop:

 Participants and their parents/guardians will use the hybrid closed-loop system with standard
 insulin aspart for 8 weeks at home. The participant, parents/guardians and the research team
 will be blinded to the intervention.

 Study contacts:

 Participants and parents/guardians will be contacted 24 hours after starting each study arm
 to ensure there are no concerns regarding the study devices. Participants will be contacted
 by the study team (email/phone) 2 and 4 weeks after the start of each study arm 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 devices or diabetes management, participants
 and parents/guardians will be able to contact a 24-hour telephone helpline to the local
 research team. The local research team will have access to central 24 hour advice on
 technical issues.

 End of study assessments:

 Height and weight will be recorded. Validated questionnaires will be completed by
 parents/guardians. Participants will resume usual care using their pre-study insulin pump.

 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 participant and parent/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 participant after consideration of the benefit/risk ratio.
 Possible reasons are:

 1. Serious adverse events

 2. Serious protocol violation

 3. Non-compliance

 4. Failure to satisfy competency assessment

 5. Decision by the investigator, or the Sponsor, that termination is in the participant's
 best medical interest

 6. Allergic reaction to insulin
Inclusion Criteria:

 1. Age between 2 and 6 years (inclusive)

 2. 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.).']

 3. Insulin pump user (with or without continuous glucose monitoring or flash glucose
 monitoring system) for at least 3 months, with parent/guardian good knowledge of
 insulin self-adjustment as judged by the investigator

 4. Treated with U-100 rapid or ultra-rapid acting insulin analogue

 5. Screening HbA1c ≤ 11% (97mmol/mol) on analysis from local laboratory

 6. Able to wear glucose sensor

 7. Able to wear closed-loop system 24/7

 8. The parent/guardian is willing to follow study specific instructions

 9. The parent/guardian is proficient in English

 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. Known or suspected allergy to insulin

 5. Parent/guardian's lack of reliable telephone facility for contact

 6. Parent/guardian's severe visual impairment

 7. Parent/guardian's severe hearing impairment

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

 9. 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)