Closed Loop From Onset in Type 1 Diabetes

Purpose of the study:

• To determine whether continued intensive metabolic control using closed loop insulin delivery (CL) following diagnosis of type 1 diabetes can preserve C-peptide secretion as a marker of residual beta cell function compared to standard multiple daily injections (MDI) therapy

Primary objective:

• To assess residual C-peptide secretion 12 months after diagnosis of type 1 diabetes in participants receiving either CL insulin delivery or standard MDI therapy

Secondary Objectives:

• Biochemical:
• To compare effects of study interventions on residual C-peptide secretion over 24 months following diagnosis
• To examine how intensive diabetes management using CL insulin delivery affects glucose control in terms of safety and efficacy over 24 months
• Human Factors: To assess cognitive, emotional, and behavioural characteristics of participating subjects and family members and their response to closed loop insulin delivery and clinical trial
• Health economics: To perform cost utility analysis and inform reimbursement decision-making

Study design:

• An open-label, multi-centre, randomised, single period, two-arm parallel group study with internal pilot, contrasting closed loop with MDI with an optional 24 month extension phase.

Sample Size:

• 96 participants randomised (48 per group); each clinical site will aim to recruit between 15 and 20 participants

Maximum duration of study for a subject:

• 24 months (48 months if opting to participate in extension phase)

Recruitment:

• Recruitment will take place at Addenbrooke's Hospital, Cambridge, Leeds Teaching Hospital, Leeds, Alder Hey Children's Hospital, Liverpool, Nottingham Hospital, Nottingham, Oxford Children's Hospital, Oxford, Southampton Children's Hospital, Southampton and Royal Hospital for Sick Children, Edinburgh..

Consent

• Written consent/assent will be obtained from participants and/or guardians according to Research Ethics Committee (REC) requirements.

Screening and baseline assessment:

Eligible participants will undergo a screening evaluation including the following activities:

• medical (diabetes) history
• body weight, height and blood pressure measurement
• record of current insulin therapy
• screening and baseline blood sampling

During a baseline visit, the following assessments/ interventions will be carried out at the clinical research facility:

• mixed meal tolerance test (MMTT)
• blood sampling for lipid profile
• centrally measured HbA1c and subsequent immunological analyses
• questionnaires
• computerised cognitive testing
• initiating blinded CGM to assess baseline glycaemic control

Run in period:

• Following consent/screening and baseline assessment, multiple daily injection therapy will be continued in all participants. All participants will receive non study related core diabetes training as per usual clinical practice for a period of up to three weeks.
• All subjects will be provided with 24 hour telephone helpline and will also be given written instructions about when to contact clinical team.

Randomisation:

• Eligible participants will be randomised in a 1:1 ratio using central randomisation software to either closed loop or standard therapy i.e. MDI.

1. Closed loop (interventional arm) Following randomisation, participants in the closed loop group will receive additional training sessions to cover key aspects of insulin pump use and CGM, prior to starting closed loop insulin delivery. Once competent in the use of the study pump and CGM system, participants will receive training required for safe and effective use of the closed loop system. During a 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 24 months without supervision or remote monitoring. The 24 hour support helpline will be available in case of problems.
2. Multiple daily injections (control arm) Participants in the control group will receive additional training sessions following randomisation including a refresher on carbohydrate counting skills, and insulin dose adjustments.

Standard therapy (i.e. MDI) will be applied for 24 months. Participants will be allowed to switch to insulin pump therapy if clinically indicated.

Follow up assessments (3-, 6-, 9-, 12-, 15-, 18-, 21- months):

• Follow up study visits will be conducted 3 monthly including data downloads/recording of insulin requirements, adverse event recording, and blood sampling (HbA1c).
• Participants 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.
• MMTTs will be performed at 6 month and 12 month follow up visit.
• Sleep will be assessed using a wristwatch device for 7 days following study visits at 6 and 12 months post diagnosis. Concomitantly, a sleep diary and sleep quality questionnaire will be distributed.
• Validated questionnaires evaluating the impact of the technology on quality of life, life change, diabetes management and fear of hypoglycaemia will be completed at the 12 month visit.
• At 12 months, participants will repeat the computerised cognitive tests first administered at baseline.
• Qualitative interviews will be conducted at month 12 in a subset of subjects and parents int he closed-loop arm.

End of study assessments (24 months):

• A MMTT will be performed.
• A blood sample will be taken for measurement of HbA1c, lipids and immunological analyses.
• Validated questionnaires evaluating the impact of the technology on quality of life, life change, diabetes management and fear of hypoglycaemia will be completed.
• Participants will repeat the computerised cognitive tests first administered at baseline.
• Sleep will be assessed using a wristwatch device for 7 days within the last month of the trial. Concomitantly, a sleep diary and sleep quality questionnaire will be distributed.
• Participants and families will be invited to attend focus group discussions. 24-hour telephone helpline:
• 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 clinical and 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 (AE) will be in place, including serious adverse events (SAE), serious adverse device effects (SADE) and specific adverse events such as severe hypoglycaemia.
• Subjects will be asked to test and record blood or urine ketones if their finger prick glucose is above 14.0 mmol/l, as part of the safety assessment for hyperglycaemia.
• A data monitoring and ethics committee (DMEC) 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 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.