Title: Effect of closed loop insulin delivery from onset of diabetes in youth on progression of type 1 diabetes
Funder: Department of Health and Social Care

Abstract: Setting: 5 paediatrics diabetes clinics. Each site will recruit 10-14 participants per year (n=20 over 22 months). Target population: Youth aged 10-17.9 yrs, with newly diagnosed T1D within previous 2 weeks. Treatments being assessed: Two forms of insulin delivery each aiming for the tightest glucose control safely achievable. (a) CL: Patients will be treated by Novorapid delivered by closed loop system overnight and between meals, with bolus doses at meal times. (b) MDI (Pen) intervention: Basal bolus analogue regimen (NovoRapid with Glargine), using a Pen Injection device. Consent will be taken for potential longer term follow-up/linkage studies. Assessments: Consented participants with T1D will be randomised to receive CL or MDI over 12 months. Study visits for both interventions will occur at baseline, 3, 6, 9, and 12 months post diagnosis. Each visit will include medication history, physical exam, urine pregnancy test (for females with reproductive potential), HbA1c assessment. At baseline and 12 months, mixed meal tolerance test (at Clinical Research Facility) will be performed and blood samples for immunological assessment taken. At 6 months, in-depth qualitative interviews will be undertaken in a subset of 15-20 parents and 15-20 youth. Primary Outcome: C-peptide area under the curve in response to a mixed meal (MMTT) at 1 year following diagnosis of type 1 diabetes. This outcome measures reliably residual insulin secretion (Greenbaum et al. 2008;Palmer et al. 2004) tightly coupled to long-term glucose control and diabetes complications (Steffes et al. 2003;The Diabetes Control and Complications Trial Research Group. 1998). Retention of residual C-peptide secretion would change clinical practice and influence NICE guidelines. Key Secondary Biomedical Outcomes: HbA1c levels over time, insulin dose, hypoglycaemia burden, severe hypoglycaemic events. Psychosocial: Perceptions of lifestyle change, diabetes management, quality of life and fear of hypoglycaemia (questionnaires), qualitative interviews. Analyses: Intention to treat (ITT), with secondary per protocol analyses. Primary endpoint is the comparison between the two treatment arms will be based on a treatment effect in an ANCOVA model adjusting for gender, presence or absence of DKA, age and baseline log(C-peptide+1). Sample size information: The primary analysis will compare the difference between groups in the levels of the 2-hour AUC-mean using the log (mean C-peptide+1). The lower 90% confidence limit for the mean log(C-peptide + 1) value is 0.315 and the upper 90% confidence limit for the RMSE is 0.167. The expected Geometric-like mean C-peptide value in the treatment arm is 0.370*1.50 = 0.555 pmol/mL. A total sample size of 88 participants provides power of 90% to detect a 50% increase in the geometric-like mean C-peptide relative to the standard treatment group using a test at the 0.05 level (two-sided) The 50% difference in the geometric-like mean C-peptide meal response is commonly accepted treatment effect of immune intervention trials (Lachin et al. 2011). Allowing for 10% loss to follow up means we would need a total of 96 participants (48 per group). Team expertise: international leaders closed loop, T1D, youth /continuous glucose monitoring/pumps, multi-centre trials, methodology, statistics.

Lay abstract: Type 1 diabetes is one of the most common lifelong conditions occurring in children and young people. Type 1 diabetes is associated with a lifelong dependency on insulin administration and on a need to maintain blood sugar levels as near to normal as possible. Achieving good diabetes control on a daily basis is challenging, and high blood sugar levels have been directly linked to an increased risk of complications of the eyes, heart, and kidneys. However attempts to achieve near-normal blood sugar levels also predispose to episodes of low blood glucose levels (hypoglycaemia). For many youth, and their parents/carers, hypoglycaemia and the fear of 'hypos' is often greater than the fear of long-term complications and is a contributing factor to their overall poor diabetes control. In Type 1 diabetes, the insulin producing organ of the body (i.e. the pancreas) stops producing sufficient amounts of insulin to regulate the body’s blood sugar levels. However, after diagnosis when blood sugar levels have been stabilised, the insulin production ability of the pancreas can temporarily improve for some months afterwards, before then faltering away completely. Retention of this residual insulin secretion as long as possible is important as it is strongly linked to improved blood sugar control, with less hypoglycaemia and with reductions in long-term diabetes complications risk. The purpose of the present study is to apply a novel approach to insulin therapy delivery called the ‘Artificial Pancreas’. The artificial pancreas (also known as a closed-loop insulin delivery system) is an emerging technology promising to transform management of Type 1 diabetes. It is based on currently available technologies, including the insulin pump and continuous glucose monitoring systems which are now commonplace in the management of patients with Type 1 diabetes. The artificial pancreas automatically delivers insulin via an insulin pump according to ‘real-time’ blood sugar levels detected by a glucose sensor. The artificial pancreas combines the glucose sensor and the insulin pump together with a computer programme to reproduce the insulin secretion patterns of a healthy pancreas. Our artificial pancreas studies to date have demonstrated that closed-loop insulin delivery can achieve near-normal blood sugar control with little risk of hypoglycaemia. We believe that application of the artificial pancreas soon after diagnosis of Type 1 diabetes and its continuous use for some months afterwards will result in sustained improvements of residual insulin secretion by the pancreas. We propose to study newly diagnosed patients with Type 1 diabetes aged 10 to 18 years. Half of the participants will be selected (at random) to be treated with standard ‘conventional’ insulin injection therapy, whilst the other half will start treatment with the artificial pancreas. Both groups will be studied for 12 months during which time blood tests for assessing residual insulin secretion will be undertaken. We will assess daily blood sugar control, including the frequency of ‘hypo’ events and will ask participants to complete Quality of Life questionnaires and to take part in qualitative structured interviews. Blood samples will also be taken to evaluate how the artificial pancreas may influence the immune system and the mechanism for preserving residual insulin secretion. Our study will be carried out at five clinic centres over a 48 month period.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE