Hybrid Closed-Loop with Faster Insulin Aspart Compared with Standard Insulin Aspart in Very Young Children with Type 1 Diabetes: A Double-Blind, Multicenter, Randomized, Crossover Study.

We evaluated the use of hybrid closed-loop (HCL) insulin delivery with faster insulin aspart (Fiasp) in very young children with type 1 diabetes (T1D). In a double-blind, multicenter, randomized, crossover study, children aged 2-6 years with T1D underwent two 8-week periods of HCL using CamAPS FX with Fiasp and standard insulin aspart (IAsp), in random order. Primary endpoint was between-treatment difference in time in target range 3.9-10.0 mmol/L. We randomized 25 participants: mean (±standard deviation) age 5.1 ± 1.3 years, baseline HbA1c 55 ± 9 mmol/mol. Time in range was not significantly different between interventions (64% ± 9% vs. 65% ± 9% for HCL with Fiasp vs. IAsp; mean difference -0.33% [95% confidence interval: -2.13 to 1.47; P = 0.71]). There was no significant difference in time with glucose <3.9 mmol/L. No post-randomization severe hypoglycemia or diabetic ketoacidosis events occurred. Use of Fiasp with CamAPS FX HCL demonstrated no significant difference in glycemic outcomes compared with IAsp in very young children with T1D. Clinical trials registration: NCT04759144.

Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation.

OBJECTIVE: To compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people. DESIGN: Pragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation. SETTING: 15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017. PARTICIPANTS: Patients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible. INTERVENTIONS: Participants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice. MAIN OUTCOME MEASURES: Primary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), paediatric quality of life inventory score, and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective. RESULTS: 294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol v 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants v 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)). CONCLUSION: During the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25.

Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT.

BACKGROUND: The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. OBJECTIVES: (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. DESIGN: A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. SETTING: Fifteen diabetes clinics in hospitals in England and Wales. PARTICIPANTS: Patients aged 7 months to 15 years. INTERVENTIONS: Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. DATA SOURCES: Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. OUTCOMES: The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs). LIMITATIONS: Generalisability beyond 12 months is uncertain. CONCLUSIONS: No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. FUTURE WORK: Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

Study protocol for a randomised controlled trial of insulin delivery by continuous subcutaneous infusion compared to multiple daily injections.

BACKGROUND: Intensive insulin therapy with continuous subcutaneous insulin infusion (CSII) devices or multiple daily injections (MDI) reduces the risk of long-term vascular complications of type I diabetes (TID). Both treatments are used routinely, but there is little evidence to demonstrate superiority of either treatment. If CSII treatment reduces the risk of long-term complications or is associated with an improved quality of life (QoL), the additional cost of this therapy may be compensated for by a reduction in long-term health expenditure. If there is no demonstrable difference between treatments, health-care resources may be better invested elsewhere. This study aims to address this gap in knowledge. METHODS/DESIGN: This is a pragmatic, randomised controlled trial (RCT). Fifteen centres, selected to represent a population with a broad demographic, will recruit 316 patients, newly diagnosed with TID, aged between 7 months and 15 years. Exclusion criteria include additional pathologies or treatments likely to affect glycaemic control and a first-degree relative with TID. Randomisation to CSII or MDI is stratified for age, gender and recruiting centre. The randomised treatment starts within 15 days of diagnosis. Patients will be trained to adjust their insulin dose according to carbohydrate intake and blood glucose level. Study visits coincide with routine clinic appointments at 3, 6, 9 and 12 months when data relating to routine clinical assessments, adverse events and concomitant medications are collected. Health utilities questionnaires are completed at each visit and a diabetes-specific QoL questionnaire (PedsQL) at diagnosis, 6 and 12 months. The primary outcome is glycaemic control (HbA1c) at 12 months. Secondary outcome measures include QoL, insulin use, growth and weight gain, adverse events and a health economics appraisal. DISCUSSION: This is the first adequately powered RCT comparing CSII and MDI in a non-selected population, treated according to standard practice guidelines. It will produce data that are meaningful to individual patients and local and national policymakers. TRIAL REGISTRATION: The study was registered with the European Clinical Trials Database on 4 November 2010, reference 2010-023792-25.