A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes.

BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes. METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (±SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53±17% at baseline to 67±10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51±16% to 55±13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group. CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).

Longevity of the novel ConvaTec infusion set with Lantern technology.

Current insulin infusion sets are approved for only 2-3 days. The novel ConvaTec infusion set with Lantern technology is designed to extend infusion set wear time. The goal of this pilot study was to evaluate the duration of wear for this set. This was a pilot safety study in adults with type 1 diabetes using tethered insulin pumps. Participants inserted the set and wore it for 10 days or until failure. Among 24 participants, two were excluded. Forty-five per cent of the sets lasted 10 days. Median wear time was 9.1 (7.1, 10.0) days. Among 12 premature failures, six (50%) involved adhesive failures, four (33%) hyperglycaemia unresponsive to correction, one (8%) hyperglycaemia with ketones and one (8%) infection. Average CGM glucose per day of infusion set wear showed a statistically significant increase over time, while total daily insulin over the same period did not change. In this pilot study, the duration of wear for the novel infusion set exceeded previously reported commercial sets (P < .001). This extended wear technology may eventually allow for a combined glucose sensor and infusion set.

Impact of Missed and Late Meal Boluses on Glycemic Outcomes in Automated Insulin Delivery-Treated Children and Adolescents with Type 1 Diabetes: A Two-Center, Population-Based Cohort Study.

Objective: To evaluate the impact of missed or late meal boluses (MLBs) on glycemic outcomes in children and adolescents with type 1 diabetes using automated insulin delivery (AID) systems. Research Design and Methods: AID-treated (Tandem Control-IQ or Medtronic MiniMed 780G) children and adolescents (aged 6-21 years) from Stanford Medical Center and Steno Diabetes Center Copenhagen with ≥10 days of data were included in this two-center, binational, population-based, retrospective, 1-month cohort study. The primary outcome was the association between the number of algorithm-detected MLBs and time in target glucose range (TIR; 70-180 mg/dL). Results: The study included 189 children and adolescents (48% females with a mean ± standard deviation age of 13 ± 4 years). Overall, the mean number of MLBs per day in the cohort was 2.2 ± 0.9. For each additional MLB per day, TIR decreased by 9.7% points (95% confidence interval [CI] 11.3; 8.1), and compared with the quartile with fewest MLBs (Q1), the quartile with most (Q4) had 22.9% less TIR (95% CI: 27.2; 18.6). The age-, sex-, and treatment modality-adjusted probability of achieving a TIR of >70% in Q4 was 1.4% compared with 74.8% in Q1 (P < 0.001). Conclusions: MLBs significantly impacted glycemic outcomes in AID-treated children and adolescents. The results emphasize the importance of maintaining a focus on bolus behavior to achieve a higher TIR and support the need for further research in technological or behavioral support tools to handle MLBs.

Automated Insulin Delivery with Remote Real-Time Continuous Glucose Monitoring for Hospitalized Patients with Diabetes: A Multicenter, Single-Arm, Feasibility Trial.

Introduction: Multiple daily injection insulin therapy frequently fails to meet hospital glycemic goals and is prone to hypoglycemia. Automated insulin delivery (AID) with remote glucose monitoring offers a solution to these shortcomings. Research Design and Methods: In a single-arm multicenter pilot trial, we tested the feasibility, safety, and effectiveness of the Omnipod 5 AID System with real-time continuous glucose monitoring (CGM) for up to 10 days in hospitalized patients with insulin-requiring diabetes on nonintensive care unit medical-surgical units. Primary endpoints included the proportion of time in automated mode and percent time-in-range (TIR 70-180 mg/dL) among participants with >48 h of CGM data. Safety endpoints included incidence of severe hypoglycemia and diabetes-related ketoacidosis (DKA). Additional glycemic endpoints, CGM accuracy, and patient satisfaction were also explored. Results: Twenty-two participants were enrolled; 18 used the system for a total of 96 days (mean 5.3 ± 3.1 days per patient), and 16 had sufficient CGM data required for analysis. Median percent time in automated mode was 95% (interquartile range 92%-98%) for the 18 system users, and the 16 participants with >48 h of CGM data achieved an overall TIR of 68% ± 16%, with 0.17% ± 0.3% time <70 mg/dL and 0.06% ± 0.2% time <54 mg/dL. Sensor mean glucose was 167 ± 21 mg/dL. There were no DKA or severe hypoglycemic events. All participants reported satisfaction with the system at study end. Conclusions: The use of AID with a disposable tubeless patch-pump along with remote real-time CGM is feasible in the hospital setting. These results warrant further investigation in randomized trials.

Impact of a Novel Diabetes Support System on a Cohort of Individuals With Type 1 Diabetes Treated With Multiple Daily Injections: A Multicenter Randomized Study.

OBJECTIVE: Achieving optimal glycemic control for many individuals with type 1 diabetes (T1D) remains challenging, even with the advent of newer management tools, including continuous glucose monitoring (CGM). Modern management of T1D generates a wealth of data; however, use of these data to optimize glycemic control remains limited. We evaluated the impact of a CGM-based decision support system (DSS) in patients with T1D using multiple daily injections (MDI). RESEARCH DESIGN AND METHODS: The studied DSS included real-time dosing advice and retrospective therapy optimization. Adults and adolescents (age >15 years) with T1D using MDI were enrolled at three sites in a 14-week randomized controlled trial of MDI + CGM + DSS versus MDI + CGM. All participants (N = 80) used degludec basal insulin and Dexcom G5 CGM. CGM-based and patient-reported outcomes were analyzed. Within the DSS group, ad hoc analysis further contrasted active versus nonactive DSS users. RESULTS: No significant differences were detected between experimental and control groups (e.g., time in range [TIR] +3.3% with CGM vs. +4.4% with DSS). Participants in both groups reported lower HbA1c (-0.3%; P = 0.001) with respect to baseline. While TIR may have improved in both groups, it was statistically significant only for DSS; the same was apparent for time spent <60 mg/dL. Active versus nonactive DSS users showed lower risk of and exposure to hypoglycemia with system use. CONCLUSIONS: Our DSS seems to be a feasible option for individuals using MDI, although the glycemic benefits associated with use need to be further investigated. System design, therapy requirements, and target population should be further refined prior to use in clinical care.

Fast-Acting Insulin Aspart Use with the MiniMedTM 670G System.

Background: This study assessed the efficacy and safety of ultrarapid insulin Fiasp® in the hybrid closed-loop MiniMed™ 670G system. Methods: This was a pilot randomized double-blinded crossover study among established MiniMed™ 670G users comparing percentage time in range (TIR) and hypoglycemia for Novolog® and Fiasp. After 2 weeks optimization with their home insulin, participants were randomized to receive Novolog or Fiasp for 2 weeks, followed by the other insulin for the next 2 weeks. Data from the second week of blinded insulin use were analyzed to allow 1 week for 670G adaptation. During the second week, individuals were asked to eat the same breakfast for 3 days to assess differences in meal pharmacodynamics. Results: Nineteen adults were recruited with mean age of 40 ± 18 years, diabetes duration of 27 ± 12 years, and median hemoglobin A1c of 7.1% (6.9, 7.5), using 0.72 (0.4, 1.2) units/(kg·day). For Novolog and Fiasp, respectively, the %TIR (70-180 mg/dL) was 75.3 ± 9.5 and 78.4 ± 9.3; %time <70 mg/dL was 3.1 ± 2.1 and 2.3 ± 2.0; %time >180 mg/dL was 21.6 ± 9.0 and 19.3 ± 8.9; mean glucose was 147 ± 12 and 146 ± 12 mg/dL; coefficient of variation was 28.6% ± 4.5% and 26.8% ± 4.4%; %time in auto mode 86.4 ± 9.2 and 84.4 ± 9.2. All comparisons were nonsignificant for insulin type. Total daily dose (Novolog 48.8 ± 28.4 vs. Fiasp 52.4 ± 31.7 units; P = 0.01) and daily basal (Novolog 17.6 [15.5, 33.8] vs. Fiasp 19.1 [15.3, 38.5] units; P = 0.07) correlated with TIR and %time >180 mg/dL. For insulin delivery in auto mode there was no statistical difference in total daily dose or daily basal between arms. Paired analysis for matched breakfast meals revealed no significant differences in time to maximum glucose, peak glucose, or glucose excursion. Conclusions: In this pilot study, the use of either Novolog or Fiasp in a commercially available MiniMed 670G system operating in auto mode resulted in clinically similar glycemic outcomes, with a slight increase in daily insulin requirements using Fiasp.

Safety and Performance of the Tandem t:slim X2 with Control-IQ Automated Insulin Delivery System in Toddlers and Preschoolers.

Background: Glycemic control is particularly challenging for toddlers and preschoolers with type 1 diabetes (T1D), and data on the use of closed-loop systems in this age range are limited. Materials and Methods: We studied use of a modified investigational version of the Tandem t:slim X2 Control-IQ system in children aged 2 to 5 years during 48 h in an outpatient supervised hotel (SH) setting followed by 3 days of home use to examine the safety of this system in young children. Meals and snacks were not restricted and boluses were estimated per parents' usual routine. At least 30 min of daily exercise was required during the SH phase. All participants were remotely monitored by study staff while on closed-loop in addition to monitoring by at least one parent throughout the study. Results: Twelve participants diagnosed with T1D for at least 3 months with mean age 4.7 ± 1.0 years (range 2.0-5.8 years) and hemoglobin A1c of 7.3% ± 0.8% were enrolled at three sites. With use of Control-IQ, the percentage of participants meeting our prespecified goals of less than 6% time below 70 mg/dL and less than 40% time above 180 mg/dL increased from 33% to 83%. Control-IQ use significantly improved percent time in range (70-180 mg/dL) compared to baseline (71.3 ± 12.5 vs. 63.7 ± 15.1, P = 0.016). All participants completed the study with no adverse events. Conclusions: In this brief pilot study, use of the modified Control-IQ system was safe in 2-5-year-old children with T1D and improved glycemic control.

Health-Related Quality of Life and Treatment Satisfaction in Parents and Children with Type 1 Diabetes Using Closed-Loop Control.

Introduction: Hybrid closed-loop systems increase time-in-range (TIR) and reduce glycemic variability. Person-reported outcomes (PROs) are essential to assess the utility of new devices and their impact on quality of life. This article focuses on the PROs for pediatric participants (ages 6-13 years) with type 1 diabetes (T1D) and their parents during a trial using the Tandem Control-IQ system, which was shown to increase TIR and improve other glycemic metrics. Research Design and Methods: One hundred and one children 6 to 13 years old with T1D were randomly assigned to closed-loop control (CLC) or sensor-augmented pump (SAP) in a 16-week randomized clinical trial with extension to 28 weeks during which the SAP group crossed over to CLC. Health-related quality of life and treatment satisfaction measures were obtained from children and their parents at baseline, 16 weeks, and 28 weeks. Results: Neither the children in the CLC group nor their parents had statistically significant changes in PRO outcomes compared with the SAP group at the end of the 16-week randomized controlled trial and the 28-week extension. Parents in the CLC group reported nonsignificant improvements in some PRO scores when compared with the SAP group at 16 weeks, which were sustained at 28 weeks. Sleep scores for parents improved from "poor sleep quality" to "adequate sleep quality" between baseline and 16 weeks, however, the change in scores was not statistically different between groups. Conclusions: Children with T1D who used the Control-IQ system did not experience increased burden compared with those using SAP based on person-reported outcomes from the children and their parents. Clinical Trials Registration: NCT03844789.

Extended Use of the Control-IQ Closed-Loop Control System in Children With Type 1 Diabetes.

OBJECTIVE: To further evaluate the safety and efficacy of the Control-IQ closed-loop control (CLC) system in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: After a 16-week randomized clinical trial (RCT) comparing CLC with sensor-augmented pump (SAP) therapy in 101 children 6-13 years old with type 1 diabetes, 22 participants in the SAP group initiated use of the CLC system (referred to as SAP-CLC cohort), and 78 participants in the CLC group continued use of CLC (CLC-CLC cohort) for 12 weeks. RESULTS: In the SAP-CLC cohort, mean percentage of time in range 70-180 mg/dL (TIR) increased from 55 ± 13% using SAP during the RCT to 65 ± 10% using CLC (P < 0.001), with 36% of the cohort achieving TIR >70% plus time <54 mg/dL <1% compared with 14% when using SAP (P = 0.03). Substantial improvement in TIR was seen after the 1st day of CLC. Time <70 mg/dL decreased from 1.80% to 1.34% (P < 0.001). In the CLC-CLC cohort, mean TIR increased from 53 ± 17% prerandomization to 67 ± 10% during the RCT and remained reasonably stable at 66 ± 10% through the 12 weeks post-RCT. No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either cohort. CONCLUSIONS: This further evaluation of the Control-IQ CLC system supports the findings of the preceding RCT that use of a closed-loop system can safely improve glycemic control in children 6-13 years old with type 1 diabetes from the 1st day of use and demonstrates that these improvements can be sustained through 28 weeks of use.

Predictors of Time-in-Range (70-180 mg/dL) Achieved Using a Closed-Loop Control System.

Background: Studies of closed-loop control (CLC) in patients with type 1 diabetes (T1D) consistently demonstrate improvements in glycemic control as measured by increased time-in-range (TIR) 70-180 mg/dL. However, clinical predictors of TIR in users of CLC systems are needed. Materials and Methods: We analyzed data from 100 children aged 6-13 years with T1D using the Tandem Control-IQ CLC system during a randomized trial or subsequent extension phase. Continuous glucose monitor data were collected at baseline and during 12-16 weeks of CLC use. Participants were stratified into quartiles of TIR on CLC to compare clinical characteristics. Results: TIR for those in the first, second, third, and fourth quartiles was 54%, 65%, 71%, and 78%, respectively. Lower baseline TIR was associated with lower TIR on CLC (r = 0.69, P < 0.001). However, lower baseline TIR was also associated with greater improvement in TIR on CLC (r = -0.81, P < 0.001). During CLC, participants in the highest versus lowest TIR-quartile administered more user-initiated boluses daily (8.5 ± 2.8 vs. 5.8 ± 2.6, P < 0.001) and received fewer automated boluses (3.5 ± 1.0 vs. 6.0 ± 1.6, P < 0.001). Participants in the lowest (vs. the highest) TIR-quartile received more insulin per body weight (1.13 ± 0.27 vs. 0.87 ± 0.20 U/kg/d, P = 0.008). However, in a multivariate model adjusting for baseline TIR, user-initiated boluses and insulin-per-body-weight were no longer significant. Conclusions: Higher baseline TIR is the strongest predictor of TIR on CLC in children with T1D. However, lower baseline TIR is associated with the greatest improvement in TIR. As with open-loop systems, user engagement is important for optimal glycemic control.

Safety and Performance of the Omnipod Hybrid Closed-Loop System in Adults, Adolescents, and Children with Type 1 Diabetes Over 5 Days Under Free-Living Conditions.

Background: The objective of this study was to assess the safety and performance of the Omnipod® personalized model predictive control (MPC) algorithm in adults, adolescents, and children aged ≥6 years with type 1 diabetes (T1D) under free-living conditions using an investigational device. Materials and Methods: A 96-h hybrid closed-loop (HCL) study was conducted in a supervised hotel/rental home setting following a 7-day outpatient standard therapy (ST) phase. Eligible participants were aged 6-65 years with A1C <10.0% using insulin pump therapy or multiple daily injections. Meals during HCL were unrestricted, with boluses administered per usual routine. There was daily physical activity. The primary endpoints were percentage of time with sensor glucose <70 and ≥250 mg/dL. Results: Participants were 11 adults, 10 adolescents, and 15 children aged (mean ± standard deviation) 28.8 ± 7.9, 14.3 ± 1.3, and 9.9 ± 1.0 years, respectively. Percentage time ≥250 mg/dL during HCL was 4.5% ± 4.2%, 3.5% ± 5.0%, and 8.6% ± 8.8% per respective age group, a 1.6-, 3.4-, and 2.0-fold reduction compared to ST (P = 0.1, P = 0.02, and P = 0.03). Percentage time <70 mg/dL during HCL was 1.9% ± 1.3%, 2.5% ± 2.0%, and 2.2% ± 1.9%, a statistically significant decrease in adults when compared to ST (P = 0.005, P = 0.3, and P = 0.3). Percentage time 70-180 mg/dL increased during HCL compared to ST, reaching significance for adolescents and children: HCL 73.7% ± 7.5% vs. ST 68.0% ± 15.6% for adults (P = 0.08), HCL 79.0% ± 12.6% vs. ST 60.6% ± 13.4% for adolescents (P = 0.01), and HCL 69.2% ± 13.5% vs. ST 54.9% ± 12.9% for children (P = 0.003). Conclusions: The Omnipod personalized MPC algorithm was safe and performed well over 5 days and 4 nights of use by a cohort of participants ranging from youth aged ≥6 years to adults with T1D under supervised free-living conditions with challenges, including daily physical activity and unrestricted meals.

Hybrid Closed-Loop Control Is Safe and Effective for People with Type 1 Diabetes Who Are at Moderate to High Risk for Hypoglycemia.

Background: Typically, closed-loop control (CLC) studies excluded patients with significant hypoglycemia. We evaluated the effectiveness of hybrid CLC (HCLC) versus sensor-augmented pump (SAP) in reducing hypoglycemia in this high-risk population. Methods: Forty-four subjects with type 1 diabetes, 25 women, 37 ± 2 years old, HbA1c 7.4% ± 0.2% (57 ± 1.5 mmol/mol), diabetes duration 19 ± 2 years, on insulin pump, were enrolled at the University of Virginia (N = 33) and Stanford University (N = 11). Eligibility: increased risk of hypoglycemia confirmed by 1 week of blinded continuous glucose monitor (CGM); randomized to 4 weeks of home use of either HCLC or SAP. Primary/secondary outcomes: risk for hypoglycemia measured by the low blood glucose index (LBGI)/CGM-based time in ranges. Results: Values reported: mean ± standard deviation. From baseline to the final week of study: LBGI decreased more on HCLC (2.51 ± 1.17 to 1.28 ± 0.5) than on SAP (2.1 ± 1.05 to 1.79 ± 0.98), P < 0.001; percent time below 70 mg/dL (3.9 mmol/L) decreased on HCLC (7.2% ± 5.3% to 2.0% ± 1.4%) but not on SAP (5.8% ± 4.7% to 4.8% ± 4.5%), P = 0.001; percent time within the target range 70-180 mg/dL (3.9-10 mmol/L) increased on HCLC (67.8% ± 13.5% to 78.2% ± 10%) but decreased on SAP (65.6% ± 12.9% to 59.6% ± 16.5%), P < 0.001; percent time above 180 mg/dL (10 mmol/L) decreased on HCLC (25.1% ± 15.3% to 19.8% ± 10.1%) but increased on SAP (28.6% ± 14.6% to 35.6% ± 17.6%), P = 0.009. Mean glucose did not change significantly on HCLC (144.9 ± 27.9 to 143.8 ± 14.4 mg/dL [8.1 ± 1.6 to 8.0 ± 0.8 mmol/L]) or SAP (152.5 ± 24.3 to 162.4 ± 28.2 [8.5 ± 1.4 to 9.0 ± 1.6]), P = ns. Conclusions: Compared with SAP therapy, HCLC reduced the risk and frequency of hypoglycemia, while improving time in target range and reducing hyperglycemia in people at moderate to high risk of hypoglycemia.