Safety and Efficacy of Sustained Automated Insulin Delivery Compared With Sensor and Pump Therapy in Adults With Type 1 Diabetes at High Risk for Hypoglycemia: A Randomized Controlled Trial.

OBJECTIVE: Assess the safety and efficacy of automated insulin delivery (AID) in adults with type 1 diabetes (T1D) at high risk for hypoglycemia. RESEARCH DESIGN AND METHODS: Participants were 72 adults with T1D who used an insulin pump with Clarke Hypoglycemia Perception Awareness scale score >3 and/or had severe hypoglycemia during the previous 6 months confirmed by time below range (TBR; defined as sensor glucose [SG] reading <70 mg/dL) of at least 5% during 2 weeks of blinded continuous glucose monitoring (CGM). Parallel-arm, randomized trial (2:1) of AID (Tandem t:slim ×2 with Control-IQ technology) versus CGM and pump therapy for 12 weeks. The primary outcome was TBR change from baseline. Secondary outcomes included time in target range (TIR; 70-180 mg/dL), time above range (TAR), mean SG reading, and time with glucose level <54 mg/dL. An optional 12-week extension with AID was offered to all participants. RESULTS: Compared with the sensor and pump (S&P), AID resulted in significant reduction of TBR by -3.7% (95% CI -4.8, -2.6), P < 0.001; an 8.6% increase in TIR (95% CI 5.2, 12.1), P < 0.001; and a -5.3% decrease in TAR (95% CI -87.7, -1.8), P = 0.004. Mean SG reading remained similar in the AID and S&P groups. During the 12-week extension, the effects of AID were sustained in the AID group and reproduced in the S&P group. Two severe hypoglycemic episodes occurred using AID. CONCLUSIONS: In adults with T1D at high risk for hypoglycemia, AID reduced the risk for hypoglycemia more than twofold, as quantified by TBR, while improving TIR and reducing hyperglycemia. Hence, AID is strongly recommended for this specific population.

Hybrid Closed Loop Overcomes the Impact of Missed or Suboptimal Meal Boluses on Glucose Control in Children with Type 1 Diabetes Compared to Sensor-Augmented Pump Therapy.

Background: It is unclear whether hybrid closed-loop (HCL) therapy attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump (SAP) therapy in children with type 1 diabetes in free-living conditions. Methods: This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL with evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an E/N HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases were analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70-180 mg/dL) according to the number of missed boluses per day. Findings: TIR was 54% ± 10% with SAP, 63% ± 7% with E/N HCL, and steadily 67% ± 7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% confidence intervals [CI] 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6-28), respectively, in the 24/7 HCL phase (P < 0.05 for all comparisons vs. SAP). Interpretation: HCL persistently improves glycemic control compared with SAP, even in case of meal bolus omission. ClinicalTrials.gov (NCT03739099).

Outcomes of hybrid closed-loop insulin delivery activated 24/7 versus evening and night in free-living prepubertal children with type 1 diabetes: A multicentre, randomized clinical trial.

AIM: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 versus only evening and night (E/N), and on extended 24/7 use, in free-living children with type 1 diabetes. MATERIALS AND METHODS: Prepubertal children (n = 122; 49 females/73 males; age, 8.6 ± 1.6 years; diabetes duration, 5.2 ± 2.3 years; insulin pump use, 4.6 ± 2.5 years; HbA1c 7.7% ± 0.7%/61 ± 5 mmol/mol) from four centres were randomized for 24/7 versus E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (TIR). RESULTS: HCL was active 94.1% and 51.1% of the time in the 24/7 and E/N modes, respectively. TIR from baseline increased more in the 24/7 versus the E/N mode (52.9% ± 9.5% to 67.3% ± 5.6% [+14.4%, 95% CI 12.4%-16.7%] vs. 55.1% ± 10.8% to 64.7% ± 7.0% [+9.6%, 95% CI 7.4%-11.6%]; P = .001). Mean percentage time below range was similarly reduced, from 4.2% and 4.6% to 2.7%, and the mean percentage time above range decreased more in the 24/7 mode (41.9% to 30.0% [-11.9%, 95% CI 9.7%-14.6%] vs. 39.8% to 32.6% [-7.2%, 95% CI 5.0%-9.9%]; P = .007). TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during the extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycaemia occurred. CONCLUSIONS: The current study shows the safety and efficacy of the Tandem Control-IQ system in free-living children with type 1 diabetes for both E/N and 24/7 use; 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issues.

DIABEO System Combining a Mobile App Software With and Without Telemonitoring Versus Standard Care: A Randomized Controlled Trial in Diabetes Patients Poorly Controlled with a Basal-Bolus Insulin Regimen.

Background: The DIABEO® system (DS) is a telemedicine solution that combines a mobile app for patients with a web portal for health care providers. DS allows real-time monitoring of basal-bolus insulin therapy as well as therapeutic decision-making, integrating both basal and bolus dose calculation. Real-life studies have shown a very low rate of use of mobile health applications by patients. Therefore, we conducted a large randomized controlled trial study to investigate the efficacy of DS in conditions close to real life (TELESAGE study). Methods: TELESAGE was a multicenter, randomized, open study with three parallel arms: arm 1 (standard care), arm 2 (DIABEO alone), and arm 3 (DIABEO+telemonitoring by trained nurses). The primary outcome assessed the reduction in HbA1c levels after a 12-month follow-up. Results: Six hundred sixty-five patients were included in the study. Participants who used DIABEO once or more times a day (DIABEO users) showed a significant and meaningful reduction of HbA1c versus standard care after a 12-month follow-up: mean difference -0.41% for arm 2-arm 1 (P = 0.001) and -0.51% for arm 3-arm 1 (P ≤ 0.001). DIABEO users included 25.1% of participants in arm 2 and 37.6% in arm 3. In the intention-to-treat population, HbA1c changes and incidence of hypoglycemia were comparable between arms. Conclusions: A clinical and statistically significant reduction in HbA1c levels was found in those patients who used DIABEO at least once a day.

Remote Monitoring of Diabetes: A Cloud-Connected Digital System for Individuals With Diabetes and Their Health Care Providers.

Benefits of telemedicine have been proven in the field of diabetes. Among a number of technical solutions, Diabeo® has been studied in both type 1 and type 2 diabetes with intensive insulin therapy. This digital therapeutic system contains a self-monitoring glucose logbook and offers automated insulin dose recommendations thanks to a fully customizable algorithm. In addition, the cloud-based dedicated software also has features to facilitate remote monitoring, including a platform for diabetes nurses who perform coaching and treatment adjustment. A detailed description of this telemedicine system is provided, as well as results of completed clinical studies. In particular, TeleDiab 1's positive results on HbA1c in type 1 diabetes are detailed. We conclude with a discussion of the role of this telemedicine system within the landscape of mobile apps for diabetes.

Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.

BACKGROUND: Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop artificial pancreas system improved glucose control compared with sensor-assisted pump therapy. METHODS: In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA1c) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556. FINDINGS: Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% [SD 9·4] than the sensor-assisted pump group (59·4% [10·2]; mean difference 9·2% [95% CI 6·4 to 11·9]; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error. INTERPRETATION: The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes. FUNDING: French Innovation Fund, Diabeloop.

Closed-loop driven by control-to-range algorithm outperforms threshold-low-glucose-suspend insulin delivery on glucose control albeit not on nocturnal hypoglycaemia in prepubertal patients with type 1 diabetes in a supervised hotel setting.

This randomized control trial investigated glucose control with closed-loop (CL) versus threshold-low-glucose-suspend (TLGS) insulin pump delivery in pre-pubertal children with type 1 diabetes in supervised hotel conditions. The patients [n = 24, age range: 7-12, HbA1c: 7.5 ± 0.5% (58 ± 5 mmol/mol)] and their parents were admitted twice at a 3-week interval. CL control to range or TLGS set at 3.9 mmoL/L were assessed for 48 hour in randomized order. Admissions included three meals and one snack, and physical exercise. Meal boluses followed individual insulin/carb ratios. While overnight (22:00-08:00) per cent continuous glucose monitoring (CGM) time below 3.9 mmol/L (primary outcome) was similar, time in ranges 3.9 to 10.0 and 3.9 to 7.8 mmoL/L and mean CGM were all significantly improved with CL (P < 0.001). These results were confirmed over the whole 48 hour. Disconnections between devices and limited accuracy of glucose sensors in the hypoglycaemic range appeared as limiting factors for optimal control. CL mode was well accepted while fear of hypoglycaemia was unchanged. CL did not minimize nocturnal hypoglycaemia exposure but improved time in target range compared to TLGS. Although safe and well-accepted, CL systems would benefit from more integrated devices.

DIABEO App Software and Telemedicine Versus Usual Follow-Up in the Treatment of Diabetic Patients: Protocol for the TELESAGE Randomized Controlled Trial.

BACKGROUND: Self-management of diabetes minimizes the risk of macrovascular and microvascular complications, but understanding and/or adherence to self-management recommendations is often suboptimal. DIABEO is a smartphone app (downloaded via the internet) used to calculate bolus insulin doses. A previous study (TELEDIAB 1) showed that the use of DIABEO was associated with a significant improvement in glycemic control in patients with poorly controlled type 1 diabetes mellitus, particularly when combined with teleconsultations with physicians. OBJECTIVE: Here, we present the protocol for a new study (Suivi A Grande Echelle d'une cohorte de diabétiques de type 1 et de type 2 sous schéma insulinique basal bolus par la TELEmédecine; abbreviated TELESAGE), conducted in a larger population of diabetic patients with poorly controlled basal-bolus insulin levels. METHODS: TELESAGE is a multicenter, double-randomized, open-label, three parallel-arms study, conducted in approximately 100 centers in France. The study will compare a control group (arm 1: usual follow-up) with two DIABEO telemedicine systems: (1) physician-assisted telemedicine (arm 2), and (2) nurse-assisted telemonitoring and teleconsultations by a diabetologist's task delegation (arm 3). Initial randomization will allocate the study arms in 12 French regions. A second randomization will assign patients in the groups allocated to each studied region. The primary objective of TELESAGE will be to investigate the effect of the DIABEO telemedicine system versus usual follow-up, with respect to improvements in the glycated hemoglobin levels of approximately 696 diabetic patients with poorly controlled basal-bolus insulin levels. RESULTS: The TELESAGE study is sponsored by Sanofi (Gentilly, France). A primary completion date is expected in June 2018, and publication of results is expected within 6 months of work completion. CONCLUSIONS: The TELESAGE study is expected to confirm the previous results of the TELEDIAB 1 study using a larger sample of diabetic patients. It is also expected to evaluate a nurse-assisted telemonitoring system. We will assess the potential of the DIABEO telemedicine service in terms of its utility and explore whether it can become an integral part of diabetes care for patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02287532; https://clinicaltrials.gov/ct2/show/NCT02287532 (Archived by WebCite at http://www.webcitation.org/6ykajhJKd).

Intraperitoneal insulin delivery provides superior glycaemic regulation to subcutaneous insulin delivery in model predictive control-based fully-automated artificial pancreas in patients with type 1 diabetes: a pilot study.

AIMS: To compare intraperitoneal (IP) to subcutaneous (SC) insulin delivery in an artificial pancreas (AP). RESEARCH DESIGN AND METHODS: Ten adults with type 1 diabetes participated in a non-randomized, non-blinded sequential AP study using the same SC glucose sensing and Zone Model Predictive Control (ZMPC) algorithm adjusted for insulin clearance. On first admission, subjects underwent closed-loop control with SC delivery of a fast-acting insulin analogue for 24 hours. Following implantation of a DiaPort IP insulin delivery system, the identical 24-hour trial was performed with IP regular insulin delivery. The clinical protocol included 3 unannounced meals with 70, 40 and 70 g carbohydrate, respectively. Primary endpoint was time spent with blood glucose (BG) in the range of 80 to 140 mg/dL (4.4-7.7 mmol/L). RESULTS: Percent of time spent within the 80 to 140 mg/dL range was significantly higher for IP delivery than for SC delivery: 39.8 ± 7.6 vs 25.6 ± 13.1 ( P = .03). Mean BG (mg/dL) and percent of time spent within the broader 70 to 180 mg/dL range were also significantly better for IP insulin: 151.0 ± 11.0 vs 190.0 ± 31.0 ( P = .004) and 65.7 ± 9.2 vs 43.9 ± 14.7 ( P = .001), respectively. Superiority of glucose control with IP insulin came from the reduced time spent in hyperglycaemia (>180 mg/dL: 32.4 ± 8.9 vs 53.5 ± 17.4, P = .014; >250 mg/dL: 5.9 ± 5.6 vs 23.0 ± 11.3, P = .0004). Higher daily doses of insulin (IU) were delivered with the IP route (43.7 ± 0.1 vs 32.3 ± 0.1, P < .001) with no increased percent time spent <70 mg/dL (IP: 2.5 ± 2.9 vs SC: 4.1 ± 5.3, P = .42). CONCLUSIONS: Glycaemic regulation with fully-automated AP delivering IP insulin was superior to that with SC insulin delivery. This pilot study provides proof-of-concept for an AP system combining a ZMPC algorithm with IP insulin delivery.

[The artificial pancreas, a dream on the point of becoming reality]. / Le pancréas artificiel, un rêve sur le point de devenir réalité.

Almost 45 000 patients with type 1 diabetes are concerned in France by outpatient insulin pump therapy. The first systems of insulin pump therapy guided by glycaemia have evolved driven by the work carried out by multi-disciplinary research teams. Today, the outpatient treatment of type 1 diabetes by an artificial pancreas is on the point of becoming reality.

Long-Term Effects of Continuous Subcutaneous Insulin Infusion on Glucose Control and Microvascular Complications in Patients With Type 1 Diabetes.

BACKGROUND: We investigated the long-term effects of continuous subcutaneous insulin infusion (CSII) on glucose control and microvascular complications in patients with type 1 diabetes (T1D). METHODS: A total of 157 patients (59 M/98 W; age 39.1 ± 14.8 years) with T1D who switched from multiple daily injections to CSII and used CSII for at least one year were included. HbA1c levels and status of microvascular complications before and while under CSII were analyzed, retrospectively. RESULTS: The follow-up period was 4.0 ± 1.5 years. HbA1c significantly decreased from 8.4 ± 1.3 to 7.7 ± 1.3% (68 ± 14 to 61 ± 14 mmol/mol) after 1-year CSII and remained lower than pre-CSII levels during four years. Patients with pre-CSII HbA1c >8.0% (64 mmol/mol) showed significant improvement of HbA1c for four years, while those with pre-CSII HbA1c <8.0% showed no significant change. The prevalence of retinopathy, albuminuria, and chronic kidney disease (CKD) were respectively 39%, 12%, and 9% at CSII initiation. During follow-up, the incidence of retinopathy, albuminuria, and CKD were 3.6, 2.5 and 1.4/100 patient-years. Onset or progression of retinopathy occurred in 16 (27.1%) patients with diabetes duration >15 years, and in three (4.3%) patients with diabetes duration <15 years ( P < .01). CONCLUSION: CSII was effective in improving HbA1c for up to four years, specifically in patients with HbA1c >8% (64 mmol/mol) prior to CSII. Incidence and progression rates of retinopathy and albuminuria were low, particularly in patients with a diabetes duration <15 years at CSII initiation. These results argue for not delaying a proposal of CSII initiation in T1D with sustained HbA1c >8% (64 mmol/mol).

Multinational Home Use of Closed-Loop Control Is Safe and Effective.

OBJECTIVE: To evaluate the efficacy of a portable, wearable, wireless artificial pancreas system (the Diabetes Assistant [DiAs] running the Unified Safety System) on glucose control at home in overnight-only and 24/7 closed-loop control (CLC) modes in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: At six clinical centers in four countries, 30 participants 18-66 years old with type 1 diabetes (43% female, 96% non-Hispanic white, median type 1 diabetes duration 19 years, median A1C 7.3%) completed the study. The protocol included a 2-week baseline sensor-augmented pump (SAP) period followed by 2 weeks of overnight-only CLC and 2 weeks of 24/7 CLC at home. Glucose control during CLC was compared with the baseline SAP. RESULTS: Glycemic control parameters for overnight-only CLC were improved during the nighttime period compared with baseline for hypoglycemia (time <70 mg/dL, primary end point median 1.1% vs. 3.0%; P < 0.001), time in target (70-180 mg/dL: 75% vs. 61%; P < 0.001), and glucose variability (coefficient of variation: 30% vs. 36%; P < 0.001). Similar improvements for day/night combined were observed with 24/7 CLC compared with baseline: 1.7% vs. 4.1%, P < 0.001; 73% vs. 65%, P < 0.001; and 34% vs. 38%, P < 0.001, respectively. CONCLUSIONS: CLC running on a smartphone (DiAs) in the home environment was safe and effective. Overnight-only CLC reduced hypoglycemia and increased time in range overnight and increased time in range during the day; 24/7 CLC reduced hypoglycemia and increased time in range both overnight and during the day. Compared with overnight-only CLC, 24/7 CLC provided additional hypoglycemia protection during the day.

Day-and-Night Closed-Loop Glucose Control in Patients With Type 1 Diabetes Under Free-Living Conditions: Results of a Single-Arm 1-Month Experience Compared With a Previously Reported Feasibility Study of Evening and Night at Home.

OBJECTIVE: After testing of a wearable artificial pancreas (AP) during evening and night (E/N-AP) under free-living conditions in patients with type 1 diabetes (T1D), we investigated AP during day and night (D/N-AP) for 1 month. RESEARCH DESIGN AND METHODS: Twenty adult patients with T1D who completed a previous randomized crossover study comparing 2-month E/N-AP versus 2-month sensor augmented pump (SAP) volunteered for 1-month D/N-AP nonrandomized extension. AP was executed by a model predictive control algorithm run by a modified smartphone wirelessly connected to a continuous glucose monitor (CGM) and insulin pump. CGM data were analyzed by intention-to-treat with percentage time-in-target (3.9-10 mmol/L) over 24 h as the primary end point. RESULTS: Time-in-target (mean ± SD, %) was similar over 24 h with D/N-AP versus E/N-AP: 64.7 ± 7.6 vs. 63.6 ± 9.9 (P = 0.79), and both were higher than with SAP: 59.7 ± 9.6 (P = 0.01 and P = 0.06, respectively). Time below 3.9 mmol/L was similarly and significantly reduced by D/N-AP and E/N-AP versus SAP (both P < 0.001). SD of blood glucose concentration (mmol/L) was lower with D/N-AP versus E/N-AP during whole daytime: 3.2 ± 0.6 vs. 3.4 ± 0.7 (P = 0.003), morning: 2.7 ± 0.5 vs. 3.1 ± 0.5 (P = 0.02), and afternoon: 3.3 ± 0.6 vs. 3.5 ± 0.8 (P = 0.07), and was lower with D/N-AP versus SAP over 24 h: 3.1 ± 0.5 vs. 3.3 ± 0.6 (P = 0.049). Insulin delivery (IU) over 24 h was higher with D/N-AP and SAP than with E/N-AP: 40.6 ± 15.5 and 42.3 ± 15.5 vs. 36.6 ± 11.6 (P = 0.03 and P = 0.0004, respectively). CONCLUSIONS: D/N-AP and E/N-AP both achieved better glucose control than SAP under free-living conditions. Although time in the different glycemic ranges was similar between D/N-AP and E/N-AP, D/N-AP further reduces glucose variability.

2 month evening and night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: a randomised crossover trial.

BACKGROUND: An artificial pancreas (AP) that can be worn at home from dinner to waking up in the morning might be safe and efficient for first routine use in patients with type 1 diabetes. We assessed the effect on glucose control with use of an AP during the evening and night plus patient-managed sensor-augmented pump therapy (SAP) during the day, versus 24 h use of patient-managed SAP only, in free-living conditions. METHODS: In a crossover study done in medical centres in France, Italy, and the Netherlands, patients aged 18-69 years with type 1 diabetes who used insulin pumps for continuous subcutaneous insulin infusion were randomly assigned to 2 months of AP use from dinner to waking up plus SAP use during the day versus 2 months of SAP use only under free-living conditions. Randomisation was achieved with a computer-generated allocation sequence with random block sizes of two, four, or six, masked to the investigator. Patients and investigators were not masked to the type of intervention. The AP consisted of a continuous glucose monitor (CGM) and insulin pump connected to a modified smartphone with a model predictive control algorithm. The primary endpoint was the percentage of time spent in the target glucose concentration range (3·9-10·0 mmol/L) from 2000 to 0800 h. CGM data for weeks 3-8 of the interventions were analysed on a modified intention-to-treat basis including patients who completed at least 6 weeks of each intervention period. The 2 month study period also allowed us to asses HbA1c as one of the secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02153190. FINDINGS: During 2000-0800 h, the mean time spent in the target range was higher with AP than with SAP use: 66·7% versus 58·1% (paired difference 8·6% [95% CI 5·8 to 11·4], p<0·0001), through a reduction in both mean time spent in hyperglycaemia (glucose concentration >10·0 mmol/L; 31·6% vs 38·5%; -6·9% [-9·8% to -3·9], p<0·0001) and in hypoglycaemia (glucose concentration <3·9 mmol/L; 1·7% vs 3·0%; -1·6% [-2·3 to -1·0], p<0·0001). Decrease in mean HbA1c during the AP period was significantly greater than during the control period (-0·3% vs -0·2%; paired difference -0·2 [95% CI -0·4 to -0·0], p=0·047), taking a period effect into account (p=0·0034). No serious adverse events occurred during this study, and none of the mild-to-moderate adverse events was related to the study intervention. INTERPRETATION: Our results support the use of AP at home as a safe and beneficial option for patients with type 1 diabetes. The HbA1c results are encouraging but preliminary. FUNDING: European Commission.

Multicenter closed-loop insulin delivery study points to challenges for keeping blood glucose in a safe range by a control algorithm in adults and adolescents with type 1 diabetes from various sites.

BACKGROUND: The Control to Range Study was a multinational artificial pancreas study designed to assess the time spent in the hypo- and hyperglycemic ranges in adults and adolescents with type 1 diabetes while under closed-loop control. The controller attempted to keep the glucose ranges between 70 and 180 mg/dL. A set of prespecified metrics was used to measure safety. RESEARCH DESIGN AND METHODS: We studied 53 individuals for approximately 22 h each during clinical research center admissions. Plasma glucose level was measured every 15-30 min (YSI clinical laboratory analyzer instrument [YSI, Inc., Yellow Springs, OH]). During the admission, subjects received three mixed meals (1 g of carbohydrate/kg of body weight; 100 g maximum) with meal announcement and automated insulin dosing by the controller. RESULTS: For adults, the mean of subjects' mean glucose levels was 159 mg/dL, and mean percentage of values 71-180 mg/dL was 66% overall (59% daytime and 82% overnight). For adolescents, the mean of subjects' mean glucose levels was 166 mg/dL, and mean percentage of values in range was 62% overall (53% daytime and 82% overnight). Whereas prespecified criteria for safety were satisfied by both groups, they were met at the individual level in adults only for combined daytime/nighttime and for isolated nighttime. Two adults and six adolescents failed to meet the daytime criterion, largely because of postmeal hyperglycemia, and another adolescent failed to meet the nighttime criterion. CONCLUSIONS: The control-to-range system performed as expected: faring better overnight than during the day and performing with variability between patients even after individualization based on patients' prior settings. The system had difficulty preventing postmeal excursions above target range.

Safety of outpatient closed-loop control: first randomized crossover trials of a wearable artificial pancreas.

OBJECTIVE: We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting. RESEARCH DESIGN AND METHODS: Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)-a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted. RESULTS: The primary outcome-reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)-resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9-10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL. CONCLUSIONS: CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety.

Assessment of Patient Perceptions About Web Telemonitoring Applied to Artificial Pancreas Use at Home.

Patients with chronic diseases as well as health care systems could benefit from telemedicine applications such as remote monitoring (RM). RM relies on a device that sends patients' health data to a remote server accessible by care teams. Recent smartphone-based artificial pancreas (AP) systems collect comprehensive set of information and could therefore support the development of RM applied to diabetes. To better understand how RM could be integrated in future AP systems, we wanted to get patients' opinion on this concept, as they are the final users of these systems. An online questionnaire with 11 items was sent to 20 experienced patients who tested AP and RM during our recent outpatient studies in France and Italy. We received 17 answers. All patients considered that during their participation in trials, RM was useful, reassuring, and essential. One-third wouldn't have participated without it. When AP is commercialized, 88% of respondents think that AP should go with a RM tool, but it should be activated only at certain times, at first use or in case of difficulties (82%). Participants ask for technical support when a device fails (88%) and for medical help in case of prolonged hyperglycemia (65%) or severe or repeated hypoglycemia (53%), but not after each case of hypoglycemia (6%). More than 75% think that RM could help them to improve their blood glucose control. This preliminary work indicates that patients expect RM to be part of future AP development. Larger studies remain to be performed to investigate its usefulness and potential economic effectiveness.

DiAs web monitoring: a real-time remote monitoring system designed for artificial pancreas outpatient trials.

BACKGROUND: Developments in an artificial pancreas (AP) for patients with type 1 diabetes have allowed a move toward performing outpatient clinical trials. "Home-like" environment implies specific protocol and system adaptations among which the introduction of remote monitoring is meaningful. We present a novel tool allowing multiple patients to monitor AP use in home-like settings. METHODS: We investigated existing systems, performed interviews of experienced clinical teams, listed required features, and drew several mockups of the user interface. The resulting application was tested on the bench before it was used in three outpatient studies representing 3480 h of remote monitoring. RESULTS: Our tool, called DiAs Web Monitoring (DWM), is a web-based application that ensures reception, storage, and display of data sent by AP systems. Continuous glucose monitoring (CGM) and insulin delivery data are presented in a colored chart to facilitate reading and interpretation. Several subjects can be monitored simultaneously on the same screen, and alerts are triggered to help detect events such as hypoglycemia or CGM failures. In the third trial, DWM received approximately 460 data per subject per hour: 77% for log messages, 5% for CGM data. More than 97% of transmissions were achieved in less than 5 min. CONCLUSIONS: Transition from a hospital setting to home-like conditions requires specific AP supervision to which remote monitoring systems can contribute valuably. DiAs Web Monitoring worked properly when tested in our outpatient studies. It could facilitate subject monitoring and even accelerate medical and technical assessment of the AP. It should now be adapted for long-term studies with an enhanced notification feature.

Day and night closed-loop control in adults with type 1 diabetes: a comparison of two closed-loop algorithms driving continuous subcutaneous insulin infusion versus patient self-management.

OBJECTIVE: To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control. RESEARCH DESIGN AND METHODS: This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals). RESULTS: Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms. CONCLUSIONS: Both CAM and iAP algorithms provide safe glycemic control.