Day and Night Closed-loop in Young People With Type 1 Diabetes (DAN05)

An Open-label, Multi-centre, Randomized, Single-period, Parallel Study to Assess the Efficacy, Safety and Utility of 6 Month Day-and-night Automated Closed-loop Insulin Delivery Under Free Living Conditions Compared to Insulin Pump Therapy in Children and Adolescents With Type 1 Diabetes

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Cambridge University Hospitals NHS Foundation Trust, University of Colorado, Denver, Indiana University, The Leeds Teaching Hospitals NHS Trust, Stanford University, Yale University, Nemours Children's Health System

The main study objective is to determine whether 24/7 automated closed-loop glucose control combined with low glucose feature will improve glucose control as measured by HbA1c. This is an open-label, multi-centre, multi-national, single-period, randomised, parallel group design study, involving a 6 month period of home study during which day and night glucose levels will be controlled either by a closed-loop system combined with low glucose feature (intervention group) or by insulin pump therapy alone (control group). It is expected that a total of up to 150 subjects (aiming for 130 randomised subjects) with type 1 diabetes will be recruited through paediatric outpatient diabetes clinics of the investigation centres. Participants will all be on subcutaneous insulin pump therapy. Subjects in the intervention group will have proven competencies both in the use of the study insulin pump and the study continuous glucose monitoring (CGM) device, and will receive appropriate training in the safe use of closed-loop insulin delivery system and low glucose feature. All subjects will have regular contact with the study team during the home study phase including 24/7 telephone support. The primary outcome is between group differences in HbA1c levels at 6 months post study arm initiation. Secondary outcomes are the time spent in the glucose target (3.9 to 10.0mmol/l; 70 to 180mg/dl), 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 of severe hypoglycaemic episodes and diabetic ketoacidosis (DKA).

Purpose of the study: To determine whether 24/7 automated closed-loop glucose control will improve glucose control as measured by glycated haemoglobin and reduce the burden of hypoglycaemia compared to insulin pump therapy alone. Study Objectives: EFFICACY: The objective is to assess efficacy of day and night automated closed-loop glucose control in improving glucose control as measured by glycated haemoglobin, as compared to insulin pump therapy alone. SAFETY: The objective is to evaluate the safety of day and night automated closed-loop glucose control, in terms of episodes of severe hypoglycaemia and other adverse events. UTILITY: The objective is to determine the frequency and duration of the use of the automated closed-loop system. HUMAN FACTORS: The objective is to assess cognitive, emotional, and behavioural characteristics of participating subjects and family members and their response to the closed-loop system and clinical trial using validated surveys and focus groups. HEALTH ECONOMICS: The objective is to perform a cost utility analysis to inform reimbursement decision-making. Study Design: An open-label, multi-centre, randomised, single-period parallel study, contrasting day-and-night automated closed-loop glucose control with insulin pump therapy alone. Population: 130 participants randomised (equal proportion of those aged 6 to 12 years and 13 to 18 years, a minimum quota of 25% participants with baseline HbA1c >8.5%) Maximum duration of study for a subject: 8 months Recruitment: The subjects will be recruited through the pediatric outpatient clinics at each center. Consent: Written consent / assent will be obtained from participants and/or guardians according to REC / IRB requirements Screening Assessments: Eligible participants will undergo a screening evaluation where blood samples for full blood count, liver, thyroid function and anti-transglutaminase antibodies (with IgA levels if not done within previous 12 months) will be taken. Non-hypoglycaemia C-peptide, glucose and HbA1c will also be measured, and a urine pregnancy test in females of child-bearing potential will be performed. Surveys investigating participants' quality of life, psychosocial and cognitive functioning, and response to their current treatment will be distributed. Participants will be fitted with a blinded continuous glucose monitoring (CGM) device to assess baseline glycaemic control. Instructions on how to safely use, remove and send back the device will be provided. Study Training: Training sessions on the use of study CGM, insulin pump (and closed loop system for those randomized to be 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 1-2 week run-in period, subjects will continue using their own insulin pump. Data obtained from blinded CGM and pump downloads may be utilised for therapy adjustment. 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. Randomization: Eligible subjects will be randomised using randomisation software to the use of real-time CGM and low glucose feature combined with day and night closed-loop or to conventional insulin pump therapy alone. A blood sample will be taken for the measurement of HbA1c and a urine pregnancy test in females of child-bearing potential. A blood sample for centralised analysis of HbA1c will be taken if screening and randomisation are >28 days apart. Automated day and night closed-loop insulin delivery (intervention arm) combined with low glucose feature (interventional arm) - Participants in the closed-loop group will receive additional training sessions following randomisation covering the use of the study insulin pump and real-time CGM, prior to starting closed-loop insulin delivery. Once confident with the use of the study pump and CGM system, participants will receive training required for safe and effective use of the closed-loop system approximately 2-4 weeks after randomisation. During this 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 6 months without direct real-time remote monitoring. Insulin pump therapy (control arm) - Refresher training on key aspects of insulin pump therapy will be provided. Subjects will continue using their own insulin pump for 6 months. 3-month and 6 month assessments: A blood sample will be taken for measurement of HbA1c and a urine pregnancy test in females of child-bearing potential. Validated surveys evaluating the impact of the devices employed on quality of life, psychosocial and cognitive functioning, diabetes management and treatment satisfaction will be completed. Participants of both study arms 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. 6 months only: Subjects/guardians will be invited to join follow-up focus groups to gather feedback and reactions to their current treatment (closed-loop or insulin pump), the clinical trial, and quality of life changes. Study Contacts: In between study visits, participants will be contacted by the study team (email or phone) once monthly in order to record any adverse events, device deficiencies, and changes in insulin settings, other medical conditions and/or medication. 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 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 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 ketones if their finger prick glucose is > 16.7mmol/l (300mg/dl) upon awakening, >300 for more than 1 hour, or >22.2mmo/l (400mg/dL) at any time as part of the safety assessment for DKA. 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 closed-loop intervention after consideration of the benefit/risk ratio. Possible reasons are: Serious adverse events Significant protocol violation or non-compliance Failure to satisfy competency assessment Decision by the investigator, or the sponsor, that termination is in the subject's best medical interest Pregnancy, planned pregnancy, or breast feeding 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.

Diabetes Mellitus, Diabetes Mellitus, Type 1, Glucose Metabolism Disorders, Endocrine System Diseases, Autoimmune Diseases

The study system includes (1) a CGM that measures glucose levels, (2) a computer program on a smartphone that determines how much insulin is needed, and (3) an insulin pump that delivers the insulin. The name of this closed-loop system used in the US is FlorenceM (Medtronic 640G pump and Guardian3 sensor). The name of this closed-loop system in the UK is FlorenceX (DANA pump and Dexcom sensor). Half of the individuals taking part in the study will use the closed-loop study system for 6 months.

The automated closed loop system (FlorenceM in US) will consist of: Next generation sensor augmented Medtronic insulin pump 640G (Medtronic Minimed, CA, USA) incorporating the Medtronic Guardian3 CGM and glucose suspend feature. The automated closed loop system (FlorenceX in UK) will consist of: The DANA Diabecare R insulin pump (Sooil Development, Korea) incorporating the Dexcom G6 CGM. An Android smartphone containing the Cambridge model predictive algorithm and communicating wirelessly with the insulin pump using a proprietary translator device.

The objective is to assess efficacy of day and night automated closed-loop glucose control combined with low glucose feature in improving HbA1c, as compared with insulin pump therapy alone.

HbA1c <7.0%, HbA1c <7.5%, Relative reduction ≥10% from baseline. o Absolute reduction ≥0.5% from baseline o Absolute reduction ≥1% from baseline o Absolute reduction ≥1% from baseline or HbA1c <7.0%

Frequency of severe hypoglycaemic episodes as defined by American Diabetes Association (adolescents), and International Society for Pediatric and Adolescent Diabetes (children), frequency of diabetic ketoacidosis (DKA), frequency of severe hyperglycaemia (>16.7 mmol/l)(>300mg/dl) with significant ketosis (plasma ketones >0.6mmol/l) and nature and severity of other adverse events

Cognitive, emotional, and behavioural characteristics of participating subjects and family members and their response to the closed-loop system and clinical trial will be assessed gathering both quantitative (validated surveys) and qualitative data (focus groups)

Cost utility analysis on the benefits of closed loop insulin delivery to inform reimbursement decision-making

Inclusion Criteria: Age ≥6 and <19 years Type 1 diabetes as defined by WHO (51) for at least 1 year [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.).'] Use of an insulin pump for at least 3 months, with good knowledge of insulin self-adjustment by subject or caregiver as judged by the investigator Using U-100 rapid acting insulin analogues insulin Aspart or Lispro only Willing to perform regular finger-prick blood glucose monitoring, with at least 4 blood glucose measurements per day day Screening HbA1c ≥ 7.0% (53 mmol/mol) and ≤10 % (86mmol/mol) based on analysis from local laboratory Literate in English Willing to wear glucose sensor Willing to wear closed-loop system at home Willing to follow study specific instructions Willing to upload pump and CGM data at regular intervals Access to WiFi. Lives with someone who is trained to administer intramuscular glucagon and is able to seek emergency assistance Exclusion Criteria: Living alone Current use of any closed-loop system 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 Untreated coeliac disease, adrenal insufficiency, or untreated thyroid disease Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic corticosteroids, non-selective beta-blockers and MAO inhibitors etc. Known or suspected allergy to insulin 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 Recurrent incidents of severe hypoglycaemia (>1 episode) during the previous 6 months (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) Recurrent incidents of diabetic ketoacidosis (>1 episode) during previous 6 months Unwilling to avoid regular use of acetaminophen Lack of reliable telephone facility for contact Total daily insulin dose ≥ 2 IU/kg/day Total daily insulin dose < 15 IU/day Pregnancy, planned pregnancy, or breast feeding Severe visual impairment Severe hearing impairment Seizure disorder Medically documented allergy towards the adhesive (glue) of plasters or unable to tolerate tape adhesive in the area of sensor placement 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) Illicit drugs abuse Subject is currently abusing prescription drugs Alcohol abuse Use of pramlintide (Symlin), or other non-insulin glucose lowering agents including sulphonylureas, biguanides, DPP4-Inhibitors, , GLP-1 analogues, SGLT-1/ 2 inhibitors at time of screening Shift work with working hours between 10pm and 8am Sickle cell disease, haemoglobinopathy, or has received red blood cell transfusion or erythropoietin within 3 months prior to time of screening Eating disorder such as anorexia or bulimia Employed by Medtronic Diabetes or with immediate family members employed by Medtronic Diabetes

Ware J, Boughton CK, Allen JM, Wilinska ME, Tauschmann M, Denvir L, Thankamony A, Campbell FM, Wadwa RP, Buckingham BA, Davis N, DiMeglio LA, Mauras N, Besser REJ, Ghatak A, Weinzimer SA, Hood KK, Fox DS, Kanapka L, Kollman C, Sibayan J, Beck RW, Hovorka R; DAN05 Consortium. Cambridge hybrid closed-loop algorithm in children and adolescents with type 1 diabetes: a multicentre 6-month randomised controlled trial. Lancet Digit Health. 2022 Apr;4(4):e245-e255. doi: 10.1016/S2589-7500(22)00020-6. Epub 2022 Mar 7.

Musolino G, Allen JM, Hartnell S, Wilinska ME, Tauschmann M, Boughton C, Campbell F, Denvir L, Trevelyan N, Wadwa P, DiMeglio L, Buckingham BA, Weinzimer S, Acerini CL, Hood K, Fox S, Kollman C, Sibayan J, Borgman S, Cheng P, Hovorka R. Assessing the efficacy, safety and utility of 6-month day-and-night automated closed-loop insulin delivery under free-living conditions compared with insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, multicentre, multinational, single-period, randomised, parallel group study protocol. BMJ Open. 2019 Jun 3;9(6):e027856. doi: 10.1136/bmjopen-2018-027856.