Randomized Trial of the Insulin-Only iLet Bionic Pancreas for the Treatment of Cystic Fibrosis- Related Diabetes.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order, crossover trial. RESEARCH DESIGN AND METHODS: Twenty participants with CFRD were assigned in random order to 14 days each on the BP or their usual care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70-180 mg/dL (time in range [TIR]) on days 3-14 of each arm, and key secondary outcomes included mean continuous glucose monitoring (CGM) glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL. RESULTS: TIR was significantly higher in the BP arm than the UC arm (75 ± 11% vs. 62 ± 22%, P = 0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150 ± 19 vs. 171 ± 45 mg/dL, P = 0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% vs. 0.36%, P = 1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs. 0.4 median episodes per day, P = 0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm. CONCLUSIONS: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared with their UC, suggesting that this may be an important therapeutic option for this patient population.

Psychosocial Impact of the Insulin-Only iLet Bionic Pancreas for Adults, Youth, and Caregivers of Youth with Type 1 Diabetes.

Objective: To evaluate the psychosocial impact and user experience for the insulin-only configuration of iLet bionic pancreas (BP) in persons 6-83 years years of age with type 1 diabetes. Research Design and Methods: In this multicenter, randomized controlled, 13-week trial, 275 adults (221 randomly assigned to the BP group and 54 to the standard of care [SC] group) and 165 youth and their caregivers (112 randomly assigned to the BP group and 53 to the SC group) completed psychosocial questionnaires at baseline, mid-study, and the end of the trial. Results: In all age groups, most participants would recommend using the BP, including those with previous experience using automated insulin delivery devices. Similarly, the vast majority of participants reported a high level of perceived benefits and a low number of perceived burdens. Adult participants reported significant decreases in the fear of hypoglycemia and in diabetes-specific emotional distress, as well as improvements in their perceived well-being. Conclusion: Findings demonstrate acceptability, reduced burden, and positive psychosocial outcomes for adults. Children and teenagers also report high acceptability and reduced burden, but less clear improvements in psychosocial outcomes. Clinical Trial Registration Number: NCT04200313.

Utility and Safety of Backup Insulin Regimens Generated by the Bionic Pancreas: A Randomized Study.

The bionic pancreas (BP) is initialized with body weight only and doses insulin autonomously without carbohydrate counting, instead using qualitative meal announcements. In case of device malfunction, the BP generates and continuously updates backup insulin doses for injection or pump users, including long-acting insulin dose, a four-period basal insulin profile, short-acting meal doses, and a glucose correction factor. Following a 13-week trial in type 1 diabetes, participants using the BP (6-83 years) completed 2-4 days, in which they were randomly assigned to their prestudy insulin regimen (N = 147) or to follow BP-provided guidance (N = 148). Glycemic outcomes with BP guidance were similar to those reinstituting their prestudy insulin regimen, with both groups having higher mean glucose and lower time-in-range than while using the BP during the 13-week trial. In conclusion, a backup insulin regimen automatically generated by the BP can be safely implemented if need arises to discontinue use of the BP. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

A Multicenter Randomized Trial Evaluating Fast-Acting Insulin Aspart in the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using fast-acting insulin aspart (Fiasp®) in adults with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized trial, 275 adults with T1D (18-83 years old, baseline HbA1c 5.3%-14.9%) were randomly assigned 2:2:1 to use the BP with fast-acting insulin aspart (BP-F group, N = 114), BP with aspart or lispro (BP-A/L group, N = 107), or a control group using their standard-care insulin delivery (SC group, N = 54) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. The BP-F versus SC comparison was considered primary and BP-F versus BP-A/L secondary. Results: Mean ± standard deviation (SD) HbA1c decreased from 7.8% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP-F versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% CI -0.7 to -0.3, P < 0.001). CGM-measured percent time <54 mg/dL over 13 weeks with BP-F was noninferior to SC (adjusted difference = 0.00%, 95% CI -0.07 to 0.05, P < 0.001 for noninferiority based on a prespecified noninferiority limit of 1%). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 14% (3.4 h/day) and mean CGM glucose was reduced by 18 mg/dL with BP-F compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and the SD of CGM glucose all favored BP-F compared with SC (P < 0.001). Differences between BP-F and BP-A/L were minimal, with no difference in HbA1c at 13 weeks (adjusted difference = -0.0%, 95% CI -0.2 to 0.1, P = 0.67) or mean glucose (adjusted difference = -2.0 mg/dL, 95% CI -4.3 to 0.4, P = 0.10). Mean TIR was 2% greater with BP-F than BP-A/L (95% CI 1 to 4, P = 0.005), but the percentages of participants improving TIR by ≥5% were not significantly different (P = 0.49) and there were no significant differences comparing BP-F versus BP-A/L across nine patient-reported outcome surveys. The rate of severe hypoglycemia events did not differ among the three groups. Conclusions: In adults with T1D, HbA1c was improved with the BP using fast-acting insulin aspart compared with standard care without increasing CGM-measured hypoglycemia. However, the effect was no better than the reduction observed with the BP using aspart or lispro. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

A Multicenter Randomized Trial Evaluating the Insulin-Only Configuration of the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using insulin aspart or insulin lispro in adults with type 1 diabetes (T1D). Methods: In this multicenter, randomized, controlled trial, 161 adults with T1D (18-79 years old, baseline HbA1c 5.5%-13.1%, 32% using multiple daily injections, 27% using a pump without automation, 5% using a pump with predictive low glucose suspend, and 36% using a hybrid closed loop system before the study) were randomly assigned 2:1 to use the BP (N = 107) with insulin aspart or insulin lispro (BP group) or a standard-of-care (SC) control group (N = 54) using their usual insulin delivery plus continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 7.6% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% confidence interval -0.6% to -0.3%, P < 0.001). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 11% (2.6 h/d) and mean CGM glucose was reduced by 16 mg/dL with BP compared with SC (P < 0.001). Improvement in these metrics was seen during the first day of BP use and by the end of the first week reached levels that remained relatively stable through 13 weeks. Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose all favored the BP group (P < 0.001). The CGM-measured hypoglycemia was low at baseline (median time <54 mg/dL of 0.21% [3 min/d] for the BP group and 0.11% [1.6 min/d] for the SC group) and not significantly different between groups over the 13 weeks (P = 0.51 for time <70 mg/dL and 0.33 for time <54 mg/dL). There were 7 (6.5% of 107 participants) severe hypoglycemic events in the BP group and 2 events in the SC group (1.9% of 54 participants, P = 0.40). Conclusions: In adults with T1D, use of the BP with insulin aspart or insulin lispro improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Insulin-Only Bionic Pancreas Pivotal Trial Extension Study: A Multi-Center Single-Arm Evaluation of the Insulin-Only Configuration of the Bionic Pancreas in Adults and Youth with Type 1 Diabetes.

Objective: To evaluate a transition from standard-of-care (SC) management of type 1 diabetes (any insulin delivery method including hybrid closed-loop systems plus real-time continuous glucose monitoring [CGM]) to use of the insulin-only configuration of the iLet® bionic pancreas (BP) in 90 adults and children (age 6-71 years). Research Design and Methods: After the SC group completed the randomized controlled trial (RCT) portion of the Insulin-Only BP Pivotal Trial, 90 of the 107 participants participated in a 13-week study using the BP. The key outcomes were change from baseline in HbA1c and CGM metrics after 13 weeks on the BP. Results: Using the BP, mean HbA1c decreased from 7.7% ± 1.0% (61 ± 10.9 mmol/mol) at baseline to 7.1% ± 0.6% (54 ± 6.6 mmol/mol) at 13 weeks (mean change -0.55% ± 0.72% [-6 ± 7.9 mmol/mol], P < 0.001), time in range 70-180 mg/dL increased by 12.0% ± 12.5% (from 53% ± 17% to 65% ± 9%, P < 0.001), and mean glucose decreased by -18 ± 23 mg/dL (from 182 ± 32 to 164 ± 15 mg/dL, P < 0.001). The higher the baseline HbA1c level, the greater the change in HbA1c. Results were similar in the adult (N = 42) and pediatric (N = 48) cohorts. Time <70 mg/dL decreased from baseline over the 13 weeks by -0.50% ± 1.86% (P = 0.02), and time <54 mg/dL was similar (change from baseline -0.08% ± 0.59%, P = 0.24). Two severe hypoglycemia events (in same participant) and one diabetic ketoacidosis event occurred. Conclusions: Glycemic control improved after adult and pediatric participants in the SC arm in the Insulin-Only BP Pivotal Trial transitioned to use of the BP. Improvement using the BP was of similar magnitude to that observed during the RCT. ClinicalTrials.gov number, NCT04200313.

Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) in youth 6-17 years old with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized, controlled trial, 165 youth with T1D (6-17 years old; baseline HbA1c 5.8%-12.2%; 35% using multiple daily injections, 36% using an insulin pump without automation, 4% using an insulin pump with low glucose suspend, and 25% using a hybrid closed-loop system before the study) were randomly assigned 2:1 to use BP (n = 112) with insulin aspart or insulin lispro (BP group) or to a control group (n = 53) using their personal standard care insulin delivery (SC group) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 8.1% ± 1.2% at baseline to 7.5% ± 0.7% at 13 weeks with BP versus 7.8% ± 1.1% at both baseline and 13 weeks with SC (adjusted difference = -0.5%, 95% CI -0.7% to -0.2%, P < 0.001). Participants with baseline HbA1c ≥9.0% (n = 34) decreased mean HbA1c from 9.7% ± 0.8% to 7.9% ± 0.6% after 13 weeks with BP compared with 9.7% ± 0.5% to 9.8% ± 0.8% with SC. Over 13 weeks, mean time in range (TIR) 70-180 mg/dL increased by 10% (2.4 h per day) and mean CGM glucose was reduced by 15 mg/dL with BP compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose favored BP (P < 0.001). Time <54 mg/dL was low at baseline (median 0.2%) and not significantly different between groups over 13 weeks (P = 0.24). A severe hypoglycemia event occurred in 3 (2.7%) participants in the BP group and in 1 (1.9%) in the SC group. Conclusions: In youth 6-17 years old with T1D, use of insulin-only configuration of BP improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Improvement in glycemic metrics was most pronounced in participants with high baseline HbA1c levels. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Bihormonal Bionic Pancreas Improves Glycemic Control in Individuals With Hyperinsulinism and Postpancreatectomy Diabetes: A Pilot Study.

OBJECTIVE: To determine whether the bihormonal bionic pancreas (BHBP) improves glycemic control and reduces hypoglycemia in individuals with congenital hyperinsulinism (HI) and postpancreatectomy diabetes (PPD) compared with usual care (UC). RESEARCH DESIGN AND METHODS: Ten subjects with HI and PPD completed this open-label, crossover pilot study. Coprimary outcomes were mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration <3.3 mmol/L. RESULTS: Mean (SD) CGM glucose concentration was 8.3 (0.7) mmol/L in the BHBP period versus 9 (1.8) mmol/L in the UC period (P = 0.13). Mean (SD) time with CGM glucose concentration <3.3 mmol/L was 0% (0.002) in the BHBP period vs. 1.3% (0.018) in the UC period (P = 0.11). CONCLUSIONS: Relative to UC, the BHBP resulted in comparable glycemic control in our population.

Automated glycemic control with the bionic pancreas in cystic fibrosis-related diabetes: A pilot study.

Cystic fibrosis-related diabetes (CFRD) is the most common extrapulmonary manifestation of cystic fibrosis. The current standard of care for CFRD involves treatment with insulin, typically via multiple daily injections. We conducted a small pilot study comparing usual care with automated glycemic control using the bihormonal (insulin and glucagon) and insulin-only configurations of the bionic pancreas. Both configurations of the bionic pancreas achieved good glycemic control, with mean glucose levels <150 mg/dl and minimal hypoglycemia. Subjects reported improved treatment satisfaction and reduced burden of diabetes management with the bionic pancreas. Further investigation of automated glycemic control in the treatment of CFRD is warranted.

Feasibility Studies of an Insulin-Only Bionic Pancreas in a Home-Use Setting.

BACKGROUND: We tested the safety and performance of the "insulin-only" configuration of the bionic pancreas (BP) closed-loop blood-glucose control system in a home-use setting to assess glycemic outcomes using different static and dynamic glucose set-points. METHOD: This is an open-label non-randomized study with three consecutive intervention periods. Participants had consecutive weeks of usual care followed by the insulin-only BP with (1) an individualized static set-point of 115 or 130 mg/dL and (2) a dynamic set-point that automatically varied within 110 to 130 mg/dL, depending on hypoglycemic risk. Human factors (HF) testing was conducted using validated surveys. The last five days of each study arm were used for data analysis. RESULTS: Thirteen participants were enrolled with a mean age of 28 years, mean A1c of 7.2%, and mean daily insulin dose of 0.6 U/kg (0.4-1.0 U/kg). The usual care arm had an average glucose of 145 ± 20 mg/dL, which increased in the static set-point arm (159 ± 8 mg/dL, P = .004) but not in the dynamic set-point arm (154 ± 10 mg/dL, P = ns). There was no significant difference in time spent in range (70-180 mg/dL) among the three study arms. There was less time <70 mg/dL with both the static (1.8% ± 1.4%, P = .009) and dynamic set-point (2.7±1.5, P = .051) arms compared to the usual-care arm (5.5% ± 4.2%). HF testing demonstrated preliminary user satisfaction and no increased risk of diabetes burden or distress. CONCLUSIONS: The insulin-only configuration of the BP using either static or dynamic set-points and initialized only with body weight performed similarly to other published insulin-only systems.

A Comparison of Time Delay in Three Continuous Glucose Monitors for Adolescents and Adults.

BACKGROUND: The physiologic delay in glucose diffusion from the blood to the interstitial fluid and instrumental factors contribute to the delay between changes in plasma glucose (PG) and measurements made by continuous glucose monitors (CGMs). This study compared the duration of this delay for three CGMs. METHODS: A total of 24 healthy adolescent and adult subjects with type 1 diabetes wore three CGM devices simultaneously for 48 hours: Dexcom G4 Platinum, Abbott Navigator, and Medtronic Enlite. The time delay between PG and CGM-estimated plasma glucose (CGMG) was estimated by comparing time-shifted CGMG with reference PG taken every 15 minutes. RESULTS: The delay estimated by our approach was larger for the Navigator than for the G4 Platinum in adolescents (7.7 ± 1.1 versus 5.6 ± 0.9 min, P = .0396) and adults (10.9 ± 1.1 versus 8.1 ± 0.7 min, P = .0107). The delay was nominally longer for the Navigator than for the Enlite in both the adolescent (7.7 ± 1.1 versus 4.3 ± 1.0 min, P = .0728) and adult (10.9 ± 1.1 versus 8.3 ± 0.9 min, P = .111) populations, but these differences were not statistically significant. There was no difference in the delay between G4 Platinum and Enlite. Adolescents had shorter delays than adults for all three devices. There was a significant correlation between longer delay and increasing age for the G4 Platinum and Navigator. CONCLUSIONS: There are differences in the estimated PG to CGMG time delays between CGM devices in the same subjects. The delay between PG and CGMG is smaller for adolescents than for adults. The PG-to-CGMG time delay is influenced by both instrument and host factors.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Day and night glycaemic control with a bionic pancreas versus conventional insulin pump therapy in preadolescent children with type 1 diabetes: a randomised crossover trial.

BACKGROUND: The safety and efficacy of continuous, multiday, automated glycaemic management has not been tested in outpatient studies of preadolescent children with type 1 diabetes. We aimed to compare the safety and efficacy of a bihormonal bionic pancreas versus conventional insulin pump therapy in this population of patients in an outpatient setting. METHODS: In this randomised, open-label, crossover study, we enrolled preadolescent children (aged 6-11 years) with type 1 diabetes (diagnosed for ≥1 year) who were on insulin pump therapy, from two diabetes camps in the USA. With the use of sealed envelopes, participants were randomly assigned in blocks of two to either 5 days with the bionic pancreas or conventional insulin pump therapy (control) as the first intervention, followed by a 3 day washout period and then 5 days with the other intervention. Study allocation was not masked. The autonomously adaptive algorithm of the bionic pancreas received data from a continuous glucose monitoring (CGM) device to control subcutaneous delivery of insulin and glucagon. Conventional insulin pump therapy was administered by the camp physicians and other clinical staff in accordance with their established protocols; participants also wore a CGM device during the control period. The coprimary outcomes, analysed by intention to treat, were mean CGM-measured glucose concentration and the proportion of time with a CGM-measured glucose concentration below 3·3 mmol/L, on days 2-5. This study is registered with ClinicalTrials.gov, number NCT02105324. FINDINGS: Between July 20, and Aug 19, 2014, 19 children with a mean age of 9·8 years (SD 1·6) participated in and completed the study. The bionic pancreas period was associated with a lower mean CGM-measured glucose concentration on days 2-5 than was the control period (7·6 mmol/L [SD 0·6] vs 9·3 mmol/L [1·7]; p=0·00037) and a lower proportion of time with a CGM-measured glucose concentration below 3·3 mmol/L on days 2-5 (1·2% [SD 1·1] vs 2·8% [1·2]; p<0·0001). The median number of carbohydrate interventions given per participant for hypoglycaemia on days 1-5 (ie, glucose <3·9 mmol/L) was lower during the bionic pancreas period than during the control period (three [range 0-8] vs five [0-14]; p=0·037). No episodes of severe hypoglycaemia were recorded. Medium-to-large concentrations of ketones (range 0·6-3·6 mmol/dL) were reported on seven occasions in five participants during the control period and on no occasion during the bionic pancreas period (p=0·063). INTERPRETATION: The improved mean glycaemia and reduced hypoglycaemia with the bionic pancreas relative to insulin pump therapy in preadolescent children with type 1 diabetes in a diabetes camp setting is a promising finding. Studies of a longer duration during which children use the bionic pancreas during their normal routines at home and school should be done to investigate the potential for use of the bionic pancreas in real-world settings. FUNDING: The Leona M and Harry B Helmsley Charitable Trust and the US National Institute of Diabetes and Digestive and Kidney Diseases.

Outpatient glycemic control with a bionic pancreas in type 1 diabetes.

BACKGROUND: The safety and effectiveness of automated glycemic management have not been tested in multiday studies under unrestricted outpatient conditions. METHODS: In two random-order, crossover studies with similar but distinct designs, we compared glycemic control with a wearable, bihormonal, automated, "bionic" pancreas (bionic-pancreas period) with glycemic control with an insulin pump (control period) for 5 days in 20 adults and 32 adolescents with type 1 diabetes mellitus. The automatically adaptive algorithm of the bionic pancreas received data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. RESULTS: Among the adults, the mean plasma glucose level over the 5-day bionic-pancreas period was 138 mg per deciliter (7.7 mmol per liter), and the mean percentage of time with a low glucose level (<70 mg per deciliter [3.9 mmol per liter]) was 4.8%. After 1 day of automatic adaptation by the bionic pancreas, the mean (±SD) glucose level on continuous monitoring was lower than the mean level during the control period (133±13 vs. 159±30 mg per deciliter [7.4±0.7 vs. 8.8±1.7 mmol per liter], P<0.001) and the percentage of time with a low glucose reading was lower (4.1% vs. 7.3%, P=0.01). Among the adolescents, the mean plasma glucose level was also lower during the bionic-pancreas period than during the control period (138±18 vs. 157±27 mg per deciliter [7.7±1.0 vs. 8.7±1.5 mmol per liter], P=0.004), but the percentage of time with a low plasma glucose reading was similar during the two periods (6.1% and 7.6%, respectively; P=0.23). The mean frequency of interventions for hypoglycemia among the adolescents was lower during the bionic-pancreas period than during the control period (one per 1.6 days vs. one per 0.8 days, P<0.001). CONCLUSIONS: As compared with an insulin pump, a wearable, automated, bihormonal, bionic pancreas improved mean glycemic levels, with less frequent hypoglycemic episodes, among both adults and adolescents with type 1 diabetes mellitus. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01762059 and NCT01833988.).

A comparative effectiveness analysis of three continuous glucose monitors: the Navigator, G4 Platinum, and Enlite.

The effectiveness and safety of continuous glucose monitors (CGMs) is dependent on their accuracy and reliability. The objective of this study was to compare 3 CGMs in adult and pediatric subjects with type 1 diabetes under closed-loop blood-glucose (BG) control. Twenty-four subjects (12 adults) with type 1 diabetes each participated in one 48-hour closed-loop BG control experiment. Venous plasma glucose (PG) measurements obtained every 15 minutes (4657 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from 3 CGMs (FreeStyle Navigator, Abbott Diabetes Care; G4 Platinum, Dexcom; Enlite, Medtronic) worn simultaneously by each subject. The Navigator and G4 Platinum (G4) had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 12.3 ± 12.1% and 10.8 ± 9.9%, respectively. Both had lower MARDs of all paired points than Enlite (17.9 ± 15.8%, P < .005). Very large errors (MARD > 50%) were less common with the G4 (0.5%) than with the Enlite (4.3%, P = .0001) while the number of very large errors with the Navigator (1.4%) was intermediate between the G4 and Enlite (P = .1 and P = .06, respectively). The average MARD for experiments in adolescent subjects were lower than in adult subjects for the Navigator and G4, while there was no difference for Enlite. All 3 devices had similar reliability. A comprehensive head-to-head-to-head comparison of 3 CGMs revealed marked differences in both accuracy and precision. The Navigator and G4 were found to outperform the Enlite in these areas.

Autonomous and continuous adaptation of a bihormonal bionic pancreas in adults and adolescents with type 1 diabetes.

CONTEXT: A challenge for automated glycemic control in type 1 diabetes (T1D) is the large variation in insulin needs between individuals and within individuals at different times in their lives. OBJECTIVES: The objectives of the study was to test the ability of a third-generation bihormonal bionic pancreas algorithm, initialized with only subject weight; to adapt automatically to the different insulin needs of adults and adolescents; and to evaluate the impact of optional, automatically adaptive meal-priming boluses. DESIGN: This was a randomized controlled trial. SETTING: The study was conducted at an inpatient clinical research center. PATIENTS: Twelve adults and 12 adolescents with T1D participated in the study. INTERVENTIONS: Subjects in each age group were randomized to automated glycemic control for 48 hours with or without automatically adaptive meal-priming boluses. MAIN OUTCOME MEASURES: Mean plasma glucose (PG), time with PG less than 60 mg/dL, and insulin total daily dose were measured. RESULTS: The 48-hour mean PG values with and without adaptive meal-priming boluses were 132 ± 9 vs 146 ± 9 mg/dL (P = .03) in adults and 162 ± 6 vs 175 ± 9 mg/dL (P = .01) in adolescents. Adaptive meal-priming boluses improved mean PG without increasing time spent with PG less than 60 mg/dL: 1.4% vs 2.3% (P = .6) in adults and 0.1% vs 0.1% (P = 1.0) in adolescents. Large increases in adaptive meal-priming boluses and shifts in the timing and size of automatic insulin doses occurred in adolescents. Much less adaptation occurred in adults. There was nearly a 4-fold variation in the total daily insulin dose across all cohorts (0.36-1.41 U/kg · d). CONCLUSIONS: A single control algorithm, initialized only with subject weight, can quickly adapt to regulate glycemia in patients with TID and highly variable insulin requirements.

A comparative effectiveness analysis of three continuous glucose monitors.

OBJECTIVE: To compare three continuous glucose monitoring (CGM) devices in subjects with type 1 diabetes under closed-loop blood glucose (BG) control. RESEARCH DESIGN AND METHODS: Six subjects with type 1 diabetes (age 52 ± 14 years, diabetes duration 32 ± 14 years) each participated in two 51-h closed-loop BG control experiments in the hospital. Venous plasma glucose (PG) measurements (GlucoScout, International Biomedical) obtained every 15 min (2,360 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from three CGM devices, the Navigator (Abbott Diabetes Care), the Seven Plus (DexCom), and the Guardian (Medtronic), worn simultaneously by each subject. Errors in paired PG-CGMG measurements and data reporting percentages were obtained for each CGM device. RESULTS: The Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 11.8 ± 11.1% and an average MARD across all 12 experiments of 11.8 ± 3.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5 ± 17.8% and 20.3 ± 18.0%, respectively, and average MARDs across all 12 experiments of 16.5 ± 6.7% and 20.2 ± 6.8%, respectively. Data reporting percentages, a measure of reliability, were 76% for the Seven Plus and nearly 100% for the Navigator and Guardian. CONCLUSIONS: A comprehensive head-to-head-to-head comparison of three CGM devices for BG values from 36 to 563 mg/dL revealed marked differences in performance characteristics that include accuracy, precision, and reliability. The Navigator outperformed the other two in these areas.

Blood glucose control in type 1 diabetes with a bihormonal bionic endocrine pancreas.

OBJECTIVE: To test whether safe and effective glycemic control could be achieved in type 1 diabetes using a bihormonal bionic endocrine pancreas driven by a continuous glucose monitor in experiments lasting more than two days and including six high-carbohydrate meals and exercise as challenges to glycemic control. RESEARCH DESIGN AND METHODS: Six subjects with type 1 diabetes and no endogenous insulin secretion participated in two 51-h experiments. Blood glucose was managed with a bionic endocrine pancreas controlling subcutaneous delivery of insulin and glucagon with insulin pumps. A partial meal-priming bolus of insulin (0.035 units/kg/meal, then 0.05 units/kg/meal in repeat experiments) was administered at the beginning of each meal (on average 78 ± 12 g of carbohydrates per meal were consumed). Plasma glucose (PG) control was evaluated with a reference quality measurement on venous blood every 15 min. RESULTS: The overall mean PG was 158 mg/dL, with 68% of PG values in the range of 70-180 mg/dL. There were no significant differences in mean PG between larger and smaller meal-priming bolus experiments. Hypoglycemia (PG <70 mg/dL) was rare, with eight incidents during 576 h of closed-loop control (0.7% of total time). During 192 h of nighttime control, mean PG was 123 mg/dL, with 93% of PG values in the range of 70-180 mg/dL and only one episode of mild hypoglycemia (minimum PG 62 mg/dL). CONCLUSIONS: A bihormonal bionic endocrine pancreas achieved excellent glycemic control with minimal hypoglycemia over the course of two days of continuous use despite high-carbohydrate meals and exercise. A trial testing a wearable version of the system under free-living conditions is justified.