Trial Conduct and Oversight

We conducted a parallel-group, unblinded, randomized trial at seven university centers in the United States. The protocol, available with the full text of this article at NEJM.org, was approved by a central institutional review board, and written informed consent (or parental consent and assent from patients who were 14 to <18 years of age) was obtained as required. An investigational device exemption was approved by the Food and Drug Administration. An independent data and safety monitoring board provided trial oversight. The first, second, and last authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol. Funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases. Tandem Diabetes Care provided the experimental closed-loop systems, supplies, and technical expertise with device issues. Tandem Diabetes Care reviewed the manuscript but was not otherwise involved in the trial design, conduct, data analysis, or manuscript preparation.

Trial Design and Patients

To be included in the trial, patients had to be at least 14 years old and have a clinical diagnosis of type 1 diabetes; they also had to have been treated with insulin for at least 1 year by means of a pump or multiple daily injections, without a restriction on the glycated hemoglobin level (complete eligibility criteria are described in Table S1 in the Supplementary Appendix, available at NEJM.org). The trial consisted of a 2-to-8-week run-in phase (with the duration dependent on whether the patient had used a pump or continuous glucose monitor previously) to collect baseline data and to train patients in the use of the devices, after which patients were randomly assigned in a 2:1 ratio to use a closed-loop system (closed-loop group) or a sensor-augmented pump (control group) for a 26-week period. The run-in phase could be skipped by patients who were already using a Dexcom continuous glucose monitor and an insulin pump (Fig. S1). Randomization was performed on the trial website with a computer-generated sequence and a permuted block design and was stratified according to site.

After randomization, each patient in the closed-loop group was trained in the use of the closed-loop system, which consisted of a pump (t:slim X2 insulin pump with Control-IQ Technology, Tandem Diabetes Care) and a continuous glucose monitor (Dexcom G6, Dexcom). This system is a third-generation descendant of DiAs — a mobile closed-loop system developed at the University of Virginia and subsequently implemented as inControl by TypeZero Technologies.9,10

Patients in the control group received a continuous glucose monitor; patients who had used a pump before participating in the trial used their personal pumps. For patients who received insulin by means of multiple daily injections, use of the pump was initiated during the run-in phase (without a low-glucose suspension feature). Patients in both treatment groups received blood glucose meters (Roche Accu-Chek Guide, Roche Diabetes Care) and ketone meters (Abbott Precision Xtra, Abbott Diabetes Care).

Patients in both groups attended follow-up visits at 2, 6, 13, and 26 weeks and were contacted by telephone at 1, 4, 9, 17, and 21 weeks. Data from the devices were downloaded and reviewed at each visit and during telephone contacts. Glycated hemoglobin was measured at each trial site (either with the use of a point-of-care device or by a local laboratory) at screening, randomization, and after 13 and 26 weeks. Glycated hemoglobin also was measured at randomization and after 13 and 26 weeks at a central laboratory at the University of Minnesota Advanced Research and Diagnostic Laboratory.

Reporting of adverse events was solicited throughout the trial. Reportable adverse events included serious adverse events, adverse events occurring in association with a trial device or procedure, severe hypoglycemia (defined as hypoglycemia leading to the need for assistance because of altered consciousness), diabetic ketoacidosis as defined by the Diabetes Control and Complications Trial,11 or hyperglycemia with ketonemia for which a health care provider was contacted.

In March 2019, use of the Control-IQ software by the closed-loop group was temporarily suspended as a precaution after a software error was found (no serious adverse events occurred); in certain instances, this error led to erroneous discontinuation of insulin delivery for up to several hours or to an erroneous bolus being given when insulin delivery restarted. Patients continued to use the system in open-loop mode until a software update was deployed to patients at home with the use of a Web-based software updater. This suspension affected 33 patients in the closed-loop group for up to 4 weeks (median, 14 days). The analyses included all data recorded during this period, even if the closed-loop mode was not in use.

Outcomes

The primary outcome was the percentage of time that the glucose level, as measured by the continuous glucose monitor, was in the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter). The main secondary outcomes, which were tested in a hierarchical fashion to maintain a type I error rate of 5%, were the percentage of time that the glucose level was greater than 180 mg per deciliter, the mean glucose concentration, the glycated hemoglobin level at 26 weeks, the percentage of time that the glucose level was less than 70 mg per deciliter, and the percentage of time that the glucose level was less than 54 mg per deciliter (3.0 mmol per liter). Continuous glucose-monitoring data, from randomization through the 26-week follow-up visit, were included in the calculation of each metric, regardless of whether the closed-loop system was active. Additional secondary outcomes, for which the type I error was controlled with the use of the false discovery rate, are listed in the statistical analysis plan. Safety outcomes included the frequency of severe hypoglycemia, diabetic ketoacidosis, and other serious adverse events.

Statistical Analysis

We calculated that a sample size of 123 patients and randomization in a 2:1 ratio (closed-loop:control) would provide 90% power with a type I error rate (two-sided) of 5% to reject the null hypothesis of no between-group difference in the percentage of time with the glucose level in the target range, under the assumption that the percentage of time in the target range in the closed-loop group would be 7.5 percentage points higher than that in the control group, with a standard deviation of 12%. The sample size was increased to 168 for an enhanced regulatory safety assessment of the closed-loop system.

Statistical analyses were performed on an intention-to-treat basis, and all patients were included in the primary analysis and all secondary analyses unless otherwise noted. For the primary analysis, the percentage of time that the glucose level was in the target range was compared between the two groups with a linear mixed-effects regression model. Analyses of the secondary outcomes that were measured with the continuous glucose monitor, glycated hemoglobin level, insulin measures, body weight, and body-mass index paralleled the primary analysis. Modification of the treatment effect according to baseline variables was assessed by including an interaction term in the models described above. The analyses of the data at 13 weeks paralleled those of the data at 26 weeks. All models and reported treatment-group differences included adjustment for the baseline level of the dependent variable, age, previous use of a continuous glucose monitor and pump, and clinical center (random effect).

Descriptive statistics include means with standard deviations and medians with interquartile ranges, depending on the distribution of data. All P values are two-tailed. Analyses were performed with SAS software, version 9.4 (SAS Institute).