Closed Loop From Onset in Type 1 Diabetes

The purpose of the study is to use a novel treatment approach, the artificial pancreas, after diagnosis of type 1 diabetes (T1D) to improve glucose control with the anticipated improvements of residual C-peptide secretion.

This is an open-label, multicentre, single-period, randomised, parallel group design study. It is expected that a total of up to 190 subjects (aiming for 96 randomised subjects) will be recruited within ten working days of diagnosis of type 1 diabetes through paediatric diabetes centres in the UK. Half of the participants aged 10 to 16.9 years will be treated by conventional insulin injections and the other half by the artificial pancreas (closed loop insulin delivery system). Each treatment will last 24 months. All participants completing the 24 month study period will be invited to continue in an optional extension phase with the treatment allocated at randomisation for a further 24 months.

Subjects in the intervention group will receive additional training on components of the artificial pancreas, i.e. insulin pump and continuous glucose monitoring (CGM), prior to starting closed loop insulin delivery. Subjects in the control intervention group will continue with standard therapy, i.e. multiple daily injection therapy. The study includes up to 14 visits and 1 telephone/email contact for subjects completing the study. After run-in and randomisation, visits will be conducted every 3 months in both arms. Beta-cell function will be assessed by serial measurement of C-peptide in response to a standardised mixed meal tolerance test (MMTT). MMTTs will be conducted at baseline, 6-,12- and 24 months post diagnosis.

The primary outcome is the between group difference in the area under the stimulated C-peptide curve (AUC) of the MMTT at 12 month post diagnosis. Secondary outcomes include between group differences in stimulated C-peptide AUC over 24 months, differences in glycaemic control as assessed by HbA1c, time spent in glucose target range, glucose variability, hypo- and hyperglycaemia as recorded by periodically applied CGM, as well as insulin requirements and change in bodyweight. Additionally, cognitive, emotional and behavioural characteristics of participating subjects and parents will be assessed, and a cost utility analysis on the benefits of closed loop insulin delivery will be performed. Safety evaluation comprises assessment of the frequency of severe hypoglycaemic episodes, diabetic ketoacidosis (DKA) and number, nature and severity of other adverse events.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Diagnosis of type 1 diabetes within previous 21 days. Day 1 will be defined as the day insulin was first administered. Type 1 diabetes will be defined according to WHO criteria using standard diagnostic practice.

   \[WHO definition: 'The aetiological type named type 1 encompasses the majority of cases with are primarily due to beta-cell destruction, and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those with beta-cell destruction for which neither an aetiology nor a pathogenesis is known (idiopathic). It does not include those forms of beta-cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects, etc.).'\]
2. The subject is at least 10 years and not older than 16.9 years
3. The subject/carer is willing to perform regular capillary blood glucose monitoring, with at least 4 blood glucose measurements taken every day
4. The subject is literate in English
5. The subject is willing to wear glucose sensor
6. The subject is willing to wear closed loop system at home
7. The subject is willing to follow study specific instructions
8. The subject is willing to upload pump and CGM data at regular intervals

Exclusion Criteria:

1. Physical or psychological condition likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator
2. Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic corticosteroids, non-selective beta-blockers and MAO inhibitors etc.
3. Known or suspected allergy to insulin
4. Regular use of acetaminophen
5. Lack of reliable telephone facility for contact
6. Pregnancy, planned pregnancy, or breast feeding
7. Living alone
8. Severe visual impairment
9. Severe hearing impairment
10. Medically documented allergy towards the adhesive (glue) of plasters or unable to tolerate tape adhesive in the area of sensor placement
11. 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
12. Illicit drugs abuse
13. Prescription drugs abuse
14. Alcohol abuse
15. Sickle cell disease, haemoglobinopathy, receiving red blood cell transfusion or erythropoietin within 3 months prior to time of screening
16. Eating disorder such as anorexia or bulimia
17. Milk protein allergy