Participants

Table 1. Table 1. Characteristics of the Study Participants at Baseline.

We screened 75 patients, of whom 58 were eligible and underwent randomization (Table 1). All the participants had a C-peptide level of less than 33 pmol per liter during the initial assessment, measured at a time when they did not have hypoglycemia (i.e., had a blood glucose level ≥72 mg per deciliter), except for four participants in the study involving children and adolescents who had levels of 40, 40, 170, and 530 pmol per liter. Four adults had stable microvascular complications, and no adult had any macrovascular complications; none of the children and adolescents had either microvascular or macrovascular complications. One adult participant and one adolescent participant voluntarily withdrew during the washout phase because of issues unrelated to the closed-loop study (Fig. S4 in the Supplementary Appendix).

End Points in the Study Involving Adults

Table 2. Table 2. Comparison of Day-and-Night and Overnight Glucose Control during Closed-Loop and Control Periods.

Figure 1. Figure 1. Sensor Glucose Levels and Insulin Delivery. Shown are the median sensor glucose levels and the median values for insulin delivery during the day-and-night closed-loop study involving adults (Panel A) and the overnight closed-loop study involving children and adolescents (Panel B). The bands indicate interquartile ranges. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

Table 2 details the primary and secondary end points in the study involving adults. The sensor glucose levels and insulin-delivery profiles are shown in Figure 1A. The proportion of time that the glycated hemoglobin level was in the target range (primary end point) was significantly greater during the intervention period than during the control period — by a mean of 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8; P<0.001). The mean glucose level was significantly lower with day-and-night use of the closed-loop system than with the control system (P<0.001), as was the time spent above the target range (P<0.001). The time that the glucose level was less than 70 mg per deciliter and less than 50 mg per deciliter (2.8 mmol per liter) was significantly less with the closed-loop system than with the control system (P=0.02 and P<0.001, respectively). The relative burden of hypoglycemia, as measured by the area under the curve when the sensor glucose level was less than 63 mg per deciliter (3.5 mmol per liter), was significantly lower by 39% (95% CI, 24 to 51) during the intervention period than during the control period (P<0.001). After adjustment of the sensor-augmented pump therapy during the run-in phase, the glycated hemoglobin level was lower during the day-and-night closed-loop insulin-delivery period than during the control period (P=0.002).

Glucose variability, measured both as the standard deviation of the sensor glucose level and as the coefficient of variation of the sensor glucose level between days, was significantly lower with day-and-night use of the closed-loop system than with the control system. During the intervention period, the time during which the glucose level was in target range was greater and the mean overnight glucose level and the glycated hemoglobin level were lower with the closed-loop system than with the control system, without an increase in the total daily insulin use (P=0.57) (Table S1 in the Supplementary Appendix). Higher basal insulin delivery during the intervention period than during the control period (P<0.001) was offset by lower bolus delivery during the intervention period (P=0.002), presumably owing to lower glucose levels that resulted in reduced correction boluses.

Insulin delivery during the daytime (8:01 a.m. to 11:59 p.m.) and overnight (midnight to 8:00 a.m.) were similar during the two study periods. The day-and-night closed-loop system was used for a median of 20.2 hours per day, and participants wore the continuous glucose monitor for a median of 22.7 hours per day. During the control period, participants wore the continuous glucose monitor for a median of 22.9 hours per day.

Figure 2. Figure 2. Overnight Glucose Levels. Shown are the individual overnight mean sensor glucose levels in adults (Panel A) and in children and adolescents (Panel B). Adults used the closed-loop systems day and night and children and adolescents used the closed-loop systems overnight. The size of the bubble indicates the proportion of time overnight during which the glucose level was below 50 mg per deciliter (2.8 mmol per liter).

Overnight end points were similar to those during the 24-hour period. The overnight mean glucose level was significantly lower with the closed-loop system than with the control system (P<0.001), and the proportion of time that the glucose level was within the overnight target range was greater with the closed-loop system (P<0.001) (Figure 2). The proportion of time that patients had hypoglycemia, the number of nights that the sensor glucose level was less than 63 mg per deciliter for at least 20 minutes, and the area under the curve when the sensor glucose level was less than 63 mg per deciliter were all significantly lower with the closed-loop system than with the control system.

The daytime end points are shown in Table S2 in the Supplementary Appendix. We observed in a lower mean glucose level, an increased proportion of time spent within the target range, and a reduced proportion of time spent above the target range. The time that the glucose level was less than 50 mg per deciliter was significantly lower with the closed-loop system than with the control therapy (P=0.02).

End Points in the Study Involving Children and Adolescents

The primary and secondary end points in the study involving children and adolescents are shown in Table 2. The sensor glucose levels and insulin-delivery profiles are shown in Figure 1B. The proportion of nocturnal time that the glucose level was in the target range (primary end point) was significantly greater during the intervention period than during the control period by a mean of 24.7 percentage points (95% CI, 20.6 to 28.7; P<0.001). The mean overnight glucose level was significantly lower with the closed-loop system than with the control system (P<0.001) (Figure 2), as was the time spent above the target range (P<0.001). The proportion of time that the sensor glucose level indicated a blood glucose level below 70 mg per deciliter was less than 4%, and the proportion of the time that the sensor glucose level indicated a blood glucose level below 50 mg per deciliter was less than 1%; these values were similar during the two study periods.

Glucose variability, as measured by the standard deviation of the overnight sensor glucose level and the coefficient of variation between nights, was significantly less with the closed-loop system than with the control system. Nocturnal glucose levels were lower during the intervention period than during the control period without an increase in the total overnight insulin dose (P=0.11) (Table S1 in the Supplementary Appendix). Daytime insulin delivery and the total daily insulin dose were similar during the two study periods. The overnight closed-loop system was operating for a median of 9.3 hours per day. Participants wore the continuous glucose monitor for a median of 22.1 hours per day during the intervention period and for a median of 20.3 hours per day during the control period (Table S3 in the Supplementary Appendix).

End points calculated over the 24-hour period are shown in Table 2. The 24-hour mean glucose level was significantly lower with overnight use of the closed-loop system than with the sensor-augmented pump therapy (P=0.01), and the proportion of time spent within the wider (70 to 180 mg per deciliter) target range was significantly greater with the closed-loop system (P<0.001). The time that the glucose level was below 50 mg per deciliter over the 24-hour period tended to be lower with the closed-loop system than with the control system (P=0.05). The burden of hypoglycemia during the 24-hour period, as measured by the area under the curve when the sensor glucose level was less than 63 mg per deciliter, was significantly lower by 42% (95% CI, 4 to 65) during the intervention period than during the control period (P=0.03).

The comparison of end points during daytime is shown in Table S2 in the Supplementary Appendix. The mean glucose level and the proportions of time spent within, above, and below the wider target range were similar during the two study periods. The area under the curve when the sensor glucose level was less than 63 mg per deciliter was significantly lower during the intervention period than during the control period (P=0.04). The time that the glucose level was below 50 mg per deciliter tended to be lower during the intervention period than during the control period (P=0.07), a finding that was attributed to the fact that the amount of time that the level was below 50 mg per deciliter was 79% (95% CI, 34 to 93) lower in the intervention period than in the control period during the post-breakfast time period (8:01 a.m. to 11:59 a.m.) (P=0.01).

Adverse Events

Table 3. Table 3. Adverse Events.

Details of all the adverse events are provided in Table 3. One episode of severe hypoglycemia occurred in an adult participant during the intervention period when the closed-loop system was not in use because of loss of connectivity (low battery) and the participant was receiving insulin at the rate supplied by the study insulin pump (Fig. S5 in the Supplementary Appendix). In the study involving children and adolescents, one adolescent participant had two severe hypoglycemic episodes (seizures) during the intervention period; these episodes required third-party assistance but did not result in hospital admission (Fig. S6 and S7 in the Supplementary Appendix). During the two episodes, the closed-loop system was not in use (closed-loop system not turned on and lack of pump connectivity) and the participant was using sensor-augmented pump therapy. The adult and adolescent participants both recovered fully, without clinical sequelae.