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

Abstract

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.

Introduction

Current hybrid closed-loop (HCL) insulin-delivery systems, which partially automate insulin delivery, have shown improved glycemic control in adults and youth with type 1 diabetes (T1D) by reducing both hyperglycemia and hypoglycemia.¹ However, hyperglycemia is still common, with time above 180 mg/dL averaging 6–7 h/day in most users.^2–6 The glucose elevation is particularly prominent postprandially, as the absorption of subcutaneously delivered rapid-acting insulin analogs is typically slower than the absorption of meal carbohydrates. Prolonged duration of action of these insulins in the absence of a counter-regulatory agent such as glucagon precludes more aggressive insulin delivery in response to hyperglycemia.

Fast-acting insulin aspart (Fiasp^®) was developed to increase the speed of insulin absorption as well as to potentially reduce the duration of action.^7,8 It contains nicotinamide to enhance initial absorption and l-arginine hydrochloride to stabilize the formulation. The active pharmaceutical ingredient in fast-acting insulin aspart and insulin aspart are identical and, therefore, once systemically absorbed, fast-acting insulin aspart has the same biological action at the insulin receptor as that of aspart. Whether these features of fast-acting insulin aspart alone can improve glycemic control in a system that automates insulin delivery is undetermined. Prior studies have suggested limited benefit,^9–12 but due to the small size of those studies, the results were not definitive.

The iLet^® bionic pancreas (BP; Beta Bionics) is an automated insulin delivery system initialized only with body weight and without any information about previous insulin dosing.^12,13 All insulin titration, including for meals, is determined autonomously by the BP insulin-dosing algorithms and cannot be modified by the user or health care provider. These algorithms continually adapt basal insulin doses, correction insulin doses, and meal-announcement doses to meet the individual's insulin needs in response to the continuous glucose monitoring (CGM) input signal to the BP. Meals are announced by the user without carbohydrate counting as “Usual For Me,” “More,” or “Less” than other meals of that type (“Breakfast,” “Lunch,” or “Dinner”) for the user. In response to these qualitative meal announcements, the system delivers ∼75% of the autonomously estimated insulin need immediately, and then will autonomously add or refrain from additional basal or correction insulin dosing postprandially, as necessary.

When CGM data are not available, the BP (1) continues to dose insulin based on a basal insulin profile autonomously determined, continually updated, and stored by the BP when CGM data were available, (2) gives meal doses as usual in response to meal announcements, and (3) gives correction doses based on manually entered capillary blood glucose values from a blood glucose meter. Insulin dosing can be maintained, increased, or temporarily suspended autonomously by the BP, in response to the entered blood-glucose values. The BP has been developed both as an insulin-only system as well as a bihormonal system that doses both insulin and glucagon.

We conducted a multicenter randomized trial of adults with T1D to evaluate the efficacy and safety of the insulin-only configuration of the BP using fast-acting insulin aspart in comparison to (1) a control group using standard-care subcutaneous insulin delivery (either multiple daily injections [MDI], an insulin pump without automation, or an insulin pump as part of an HCL system) in conjunction with real-time CGM and (2) a group using the BP with either insulin aspart or insulin lispro.

Methods

This parallel group multicenter randomized trial in adults was conducted at 16 diabetes centers in the United States as part of a larger study¹⁴ whose primary aim was to evaluate the BP using aspart or lispro versus standard care in a cohort, including both adult and pediatric participants with T1D. The protocol was approved by a central Institutional Review Board and informed consent was obtained from each participant. An investigational device exemption for the conduct of the trial was approved by the U.S. Food and Drug Administration (FDA). The full protocol is available at https://www.jaeb.org/finaliobp and key aspects are summarized herein.

To be eligible for the trial, participants had to be ≥18 years old, with a diagnosis of T1D, and treated with insulin for at least 1 year by MDI or pump therapy with or without CGM or HCL. There was no restriction on HbA1c level and no exclusion for prior severe hypoglycemia events or prior diabetic ketoacidosis events. SGLT2 inhibitors were prohibited and GLP1 agonists were allowed if the dose was stable for 3 months and the participant was willing to discontinue if assigned to use the BP. A complete list of inclusion and exclusion criteria are provided in Supplementary Table S1. To enroll participants with characteristics as similar as possible to the general population of people with T1D, recruitment goals included minimums of 33% of MDI users, 33% with HbA1c ≥8.0%, and 33% with age ≥50 years; and a maximum of 20% with HbA1c <7.0%.

Participants using a personal Dexcom G6 CGM System (Dexcom, Inc.) who had ≥85% of possible glucose data during the 14 days before the screening visit could proceed directly to randomization once eligibility was confirmed. All other participants completed a 14-day baseline data collection period using a Dexcom G6 CGM and were required to have at least 85% of CGM values during the 14 days before proceeding to randomization. Participants using a Dexcom G5 or G6 CGM used an unblinded G6 CGM while all others wore a blinded G6 CGM. If participants used a non-Dexcom CGM, they were encouraged to continue its use during the baseline data collection period (while wearing the blinded Dexcom CGM).

Randomization was performed on the study website using a computer-generated sequence with a permuted block design, stratified by site. Participants were randomly assigned in a 2:2:1 ratio to treatment with the BP with fast-acting insulin aspart (BP-F group), the BP with insulin aspart or insulin lispro (BP-A/L group), or standard care (SC group) with an unblinded Dexcom G6 CGM.

Participants assigned to the two BP groups were provided with the iLet that is part of the BP system, Dexcom G6 sensors and transmitters, insulin infusion sets (Inset I, Unomedical) to deliver insulin subcutaneously, a Contour^®Next One Blood Glucose Monitoring System (Ascensia Diabetes Care, Basel, CH) and test strips, and a Precision Xtra ketone meter (Abbott Diabetes Care) and test strips. The BP-F group was provided with fast-acting insulin aspart in 1.6-mL glass, prefilled cartridges. The BP-A/L group filled 1.6-mL glass, ready-to-fill cartridges with their personal insulin aspart or insulin lispro if used from vials; if they used pens or a different insulin, the study provided them with insulin aspart or insulin lispro in 10-mL vials.

The insulin-dosing algorithms were identical for the BP-F and BP-A/L groups. The BP groups were trained on the use of the BP system and given specific written instructions for identifying and managing possible infusion set failures, which included a “ketone action plan” if instances of prolonged hyperglycemia arose. There were no restrictions on diet or exercise during the trial period.

The algorithms were initialized only by entering the participant's body weight; there was no run-in or warm-up period for the device before automation of insulin delivery commenced. The default glucose target of “Usual” (120 mg/dL, 6.7 mmol/L) could be shifted by ±10 mg/dL (0.56 mmol/L), down to “Lower” or up to “Higher”; a different target from the default target could be set for part of the day at the discretion of the study physician.

Participants assigned to the SC group continued to use their prestudy personal insulin delivery method and insulin regimen, which could include MDI, an insulin pump without automation, or an FDA-approved/cleared HCL system. All participants used an unblinded Dexcom G6 CGM for daily glucose monitoring, with study-provided sensors and transmitters. If they previously used a different CGM system, they could continue its use in addition to the Dexcom G6, at their discretion. CGM-naive participants in the SC group were trained in the insertion and maintenance of the Dexcom G6 CGM and in the interpretation and use of CGM data.

Participants in the SC group were not provided with a study blood glucose meter or a ketone meter and were not provided with, or trained on, the ketone action plan for management of potential infusion set failures that was provided to the BP group. Diabetes management for participants in the SC group, including any adjustments to their insulin regimen and management of problems such as infusion set failures, was done by their own diabetes care providers, not study staff.

After randomization, participants in all three groups had phone contacts after 1–2 days and 1 week and had follow-up visits at 2, 6, 10, and 13 weeks. Some visits were completed remotely via video conference due to the COVID pandemic. Data from the BP were downloaded at weeks 6 and 13 when these were in-person, or when the BP was shipped back to the study site whenever the week-13 visit was done by video conference. Blood samples from venipuncture or fingerstick¹⁵ were collected at randomization and after 6 and 13 weeks for measurement of HbA1c by a central laboratory at the University of Minnesota Advanced Research and Diagnostic Laboratory (measured with a Tosoh BioScience instrument). Patient-reported outcome surveys were completed at baseline and during follow-up (listed in Supplementary Table S22); comparisons of BP-F versus BP-A/L are reported herein and comparisons of BP-F versus SC will be reported separately.

Reporting of adverse events was solicited throughout the trial. Severe hypoglycemia was defined as hypoglycemia requiring assistance because of altered consciousness. Diabetic ketoacidosis was defined by the criteria established by the Diabetes Control and Complications Trial.¹⁶

Statistical methods

For the purposes of this article, the main analysis was a comparison of the BP-F and SC groups. The BP-F versus BP-A/L comparison was an exploratory analysis as prespecified in the study statistical analysis plan. Comparison of the BP-A/L group versus SC group is reported elsewhere.¹⁴ HbA1c was the primary outcome and noninferiority for CGM-measured time <54 mg/dL was a key secondary outcome (with noninferiority limit of 1%). For the BP-F versus SC comparisons, to control the type 1 error, these outcomes were tested in a hierarchal manner followed by the outcomes included in Table 2. For all other BP-F versus SC and all BP-F versus BP-A/L comparisons, the type I error was controlled with the use of the adaptive Benjamini-Hochberg false discovery rate correction procedure.¹⁷

Table 2.

Primary and Key Secondary Outcomes

	SC group baseline/follow up	BP-F group baseline/follow-up	BP-A/L group baseline/follow-up	BP-F versus SC	BP-F versus BP-A/L
				13w adjusted group difference (95% CI) [P]a
	N = 53/53	N = 113/111	N = 107/102
HbA1c, mean (SD)	7.6 (1.2)/7.5 (0.9)	7.8 (1.2)/7.1 (0.6)	7.6 (1.2)/7.1 (0.6)	−0.5% (−0.7% to −0.3) [<0.001]	−0.0 (−0.2 to 0.1) [0.67]
	N = 54/54	N = 114/113	N = 107/106
CGM metrics
Time <54 mg/dL (noninferiorityb), median (IQR)	0.11% (0.00%, 0.37%)/0.18% (0.08%, 0.58%)	0.12% (0.02%, 0.68%)/0.26% (0.12%, 0.48%)	0.21% (0.02%, 0.57%)/0.33% (0.14%, 0.52%)	0.00% (−0.07 to 0.05) [<0.001]	−0.04% (−0.11 to 0.01) [<0.001]
Mean glucose, mg/dL, mean (SD)	186 (42)/174 (30)	181 (34)/155 (11)	179 (41)/157 (12)	−18 (−22 to −14) [<0.001]	−2.0 (−4.3 to 0.4) [0.10]
Time 70–180 mg/dL, mean (SD)	53% (21%)/58% (17%)	54% (18%)/71% (8%)	56% (19%)/69% (8%)	14% (11 to 17) [<0.001]	2% (1 to 4) [0.005]
Time >180 mg/dL, mean (SD)	45% (21%)/40% (18%)	43% (19%)/27% (8%)	42% (20%)/28% (9%)	−13% (−16 to −10) [<0.001]	−2% (−4 to −0%) [0.01]
Time >250 mg/dL, median (IQR)	13.2% (3.8%, 32.0%)/10.4% (4.3%, 23.6%)	13.1% (6.0%, 24.1%)/4.8% (2.7%, 7.6%)	11.0% (4.9%, 23.0%)/5.4% (3.4%, 7.7%)	−5.0% (−7.0 to −3.3) [<0.001]	−1.0% (−1.6 to −0.3) [0.003]
Standard deviation, mg/dL, mean (SD)	65 (18)/61 (14)	64 (16)/52 (9)	62 (16)/54 (9)	−10 (−12 to −7) [<0.001]	−3 (−5 to −1) [0.002]
Time <70 mg/dL, median (IQR)	1.3% (0.4%, 2.6%)/1.5% (0.6%, 2.7%)	1.3% (0.4%, 3.4%)/1.7% (1.0%, 2.5%)	1.7% (0.5%, 2.8%)/1.9% (1.1%, 2.8%)	−0.1% (−0.4 to 0.2) [0.54c]	−0.2 (−0.5 to 0.0) [0.08]
Time <54 mg/dL, median (IQR)	0.11% (0.00%, 0.37%)/0.18% (0.08%, 0.58%)	0.12% (0.02%, 0.68%)/0.26% (0.12%, 0.48%)	0.21% (0.02%, 0.57%)/0.33% (0.14%, 0.52%)	0.00% (−0.07 to 0.05)	−0.04% (−0.11 to 0.01) [0.11]
Coefficient of variation, mean (SD)	35% (5%)/35% (5%)	35% (6%)/33% (4%)	35% (6%)/34% (4%)	−2.2% (−3.4 to −1.0%)	−1.4% (−2.4 to −0.4) [0.006]

Baseline HbA1c was missing for 1, 1, and 0 participants in the BP-F, SC, and BP-A/L groups, respectively, and week 13 HbA1c was missing for 3, 1, and 5, respectively. One participant in the BP-F group and one participant in the BP-A/L group were missing follow-up CGM data. All participants were included in the models.

^a From a mixed effect model adjusting for baseline value of the metric, age at randomization, and site (random effect). Missing data was handled using direct likelihood analyses. Due to a skewed distribution, % time >250, <70, and <54 mg/dL were transformed using a rank normal transformation. To control the type 1 error, a hierarchical approach was used in which hypothesis testing was performed sequentially in the order listed in the table. When a P-value ≥0.05 was observed, end points below on the list were not formally tested. Adjusted difference is BP-F minus SC or BP-A/L.

^b P-value from testing for non-inferiority with margin of 1.0%. All other p-values reflect testing for superiority.

^c Due to hierarchical testing procedure, outcomes stopped testing at time <70 mg/dL for the BP-F versus SC comparison; therefore, P-values are not reported for time <54 mg/dL (superiority) and coefficient of variation. The BP-F versus BP-A/L comparison was considered exploratory and was not subjected to the hierarchical testing approach. Multiple comparisons for BP-F versus BP-A/L were instead adjusted using the Benjamini-Hochberg adaptive false discovery rate correction procedure.

CI, confidence interval; IQR, interquartile range.

Assumptions underlying the power calculations for these two outcomes are provided in Supplementary Table S2. The study was planned to include 275 adult participants, with ∼110 assigned to each of the BP groups and 55 to the SC group.

Statistical analyses were performed on an intention-to-treat basis. Continuous outcomes were compared between groups using linear mixed effects regression models and binary outcomes with logistic regression models, adjusting for the baseline value of the metric, age, and clinical center (random effect). Modification of the treatment effect by baseline variables was assessed by including an interaction term in the models described above. For key safety outcomes, when at least five events occurred combined between groups, treatment group comparisons were made using a Poisson regression model adjusting for baseline age, baseline HbA1c, site as a random effect, and for the severe hypoglycemia outcome, prior severe hypoglycemia events. Per-protocol and sensitivity analyses were performed as described in Supplementary Table S2.

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

Results

Between January 4, 2021, and July 7, 2021, a total of 275 adult participants were randomly assigned to the BP-F group (N = 114), BP-A/L group (N = 107), or the SC group (N = 54). Participant age ranged from 18 to 83 (mean 43 ± 16), with 51% being female and 84% non-Hispanic white. Baseline HbA1c ranged from 5.3% to 14.9% (mean 7.7 ± 1.2). At study entry, 84% were using CGM; insulin delivery was by MDI in 33%, by pump without automation in 27%, by pump with predictive low glucose suspend in 5%, and by an HCL system in 35%. Characteristics of the three treatment groups are shown in Table 1.

Table 1.

Participant Characteristics by Treatment Group

	SC (N = 54), n (%)	BP-F (N = 114), n (%)	BP-A/L (N = 107), n (%)
Age, years
Mean (SD)	44 (16)	42 (16)	44 (15)
18 to <25	7 (13)	21 (18)	16 (15)
25 to <45	21 (39)	46 (40)	38 (36)
45 to <60	13 (24)	29 (25)	33 (31)
≥60	13 (24)	18 (16)	20 (19)
Range	18–79	18–83	18–73
Diabetes duration, years, mean (SD)	29 (14)	24 (14)	26 (14)
HbA1c level at randomization, %a
Mean (SD)	7.6 (1.2)	7.8 (1.2)	7.6 (1.2)
≤7.0	18 (34)	31 (27)	37 (35)
7.1 to 7.4	6 (11)	17 (15)	17 (16)
7.5 to 9.4	26 (49)	56 (50)	46 (43)
≥9.5	3 (6)	9 (8)	7 (7)
Range	5.5–11.3	5.3–14.9	5.5–13.1
Sex: female	26 (48)	62 (54)	52 (49)
Race/ethnicity group
White non-Hispanic	47 (87)	98 (86)	85 (79)
Black non-Hispanic	2 (4)	10 (9)	14 (13)
Hispanic or Latino	3 (6)	6 (5)	7 (7)
Asian	1 (2)	0 (0)	0 (0)
American Indian/Alaskan Native	1 (2)	0 (0)	0 (0)
More than one race	0 (0)	0 (0)	1 (<1)
Unknown/not reported	0 (0)	0 (0)	0 (0)
Annual household income
< $25,000	1 (2)	1 (<1)	3 (3)
$25,000 to <$35,000	5 (9)	7 (6)	3 (3)
$35,000 to <$50,000	2 (4)	4 (4)	4 (4)
$50,000 to <$75,000	4 (7)	14 (12)	18 (17)
$75,000 to <$100,000	8 (15)	19 (17)	9 (8)
$100,000 to <$200,000	12 (22)	38 (33)	41 (38)
≥ $200,000	12 (22)	15 (13)	17 (16)
Unknown/does not wish to provide	10 (19)	16 (14)	12 (11)
Education
<Bachelor's	21 (39)	47 (41)	35 (33)
Bachelor's	22 (41)	47 (41)	40 (37)
>Bachelor's	10 (19)	19 (17)	30 (28)
Unknown/does not wish to provide	1 (2)	1 (<1)	2 (2)
Health insurance
Private	45 (83)	98 (86)	94 (88)
Medicare/Medicaid	6 (11)	10 (9)	9 (8)
Other government insurance	2 (4)	2 (2)	2 (2)
None	1 (2)	2 (2)	0 (0)
Did not provide/unknown	0 (0)	2 (2)	2 (2)
Body mass index, kg/m2a
Mean (SD)	29.1 (6.9)	28.6 (5.1)	28.9 (5.5)
<18.5	2 (4)	0 (0)	0 (0)
18.5 to 24.9	16 (30)	32 (28)	29 (27)
25.0 to 29.9	14 (26)	41 (36)	40 (37)
≥30.0	22 (41)	40 (35)	38 (36)
Insulin/CGM device use
MDI without CGM	6 (11)	7 (6)	13 (12)
MDI with CGM	12 (22)	32 (28)	21 (20)
Pump without CGM	3 (6)	10 (9)	5 (5)
Pump with CGM (without automation)	14 (26)	22 (19)	21 (20)
Pump with CGM with predictive low glucose suspend feature	2 (4)	5 (4)	6 (6)
Hybrid closed-loop system	17 (31)	38 (33)	41 (38)
Currently using CGM	45 (83)	97 (85)	89 (83)
c-Peptide,a ng/mL
Mean (SD)	0.009 (0.023)	0.025 (0.070)	0.046 (0.185)
<0.007	46 (92)	80 (78)	77 (78)
Total daily insulin,a U/(kg·day), median (IQR)	0.65 (0.50, 0.83)	0.60 (0.49, 0.76)	0.60 (0.47, 0.76)
Time since last severe hypoglycemia eventb
Never had an event	17 (31)	57 (50)	48 (45)
<3 months ago	0 (0)	1 (<1)	4 (4)
3 to <6 months ago	1 (2)	1 (<1)	0 (0)
≥6 months ago	36 (67)	55 (48)	55 (51)
Time since last diabetic ketoacidosis event
Never had an event	22 (41)	46 (40)	57 (53)
<3 months ago	0 (0)	0 (0)	1 (<1)
3 to <6 months ago	0 (0)	0 (0)	0 (0)
≥6 months ago	32 (59)	68 (60)	49 (46)
Non-insulin glucose-lowering medications in use at time of randomization
None	52 (96)	110 (96)	98 (92)
Metformin	2 (4)	4 (4)	7 (7)
GLP1 agonist	0 (0)	0 (0)	2 (2)

^a HbA1c missing for one BP-F and one SC participant. Body mass index missing for one BP-F participant. c-Peptide missing for 11 BP-F participants, 4 SC participants, and 8 BP-A/L participants. Total daily insulin missing for one BP-F participant.

^b A severe hypoglycemic event is defined as a hypoglycemic event that (a) required assistance of another person due to altered consciousness, and (b) required another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

BP-A/L, BP with aspart or lispro; BP-F, BP with fast-acting insulin aspart; CGM, continuous glucose monitoring; MDI, multiple daily injection; SC, standard care; SD, standard deviation.

The trial was completed by 271 (98.5%) of the 275 participants (Supplementary Fig. S1), and the overall visit and phone contact completion rate was 99%. One or more unscheduled visits or contacts occurred for 82 (72%) of the 114 participants in the BP-F group, 82 (77%) of the 107 participants in the BP-A/L group, and 19 (35%) of the 54 participants in the SC group (Supplementary Table S3). Most of the unscheduled visits or contacts in the BP groups were due to a question or problem with diabetes management, a device deficiency/issue, or a potential adverse event (Supplementary Table S4).

One participant in the BP-F group withdrew from the study on the day of randomization during the training on use of the BP and did not initiate use of the system. In addition to the participants who used the BP but withdrew from the study before 13 weeks (three in the BP-A/L group), seven other participants in the BP-F group and eight in the BP-A/L group completed the trial but discontinued using the BP before the end of the trial. Reasons for discontinuation are indicated in Supplementary Table S5. The percentages of time that the BP was autonomously dosing insulin was similar in the BP-F and BP-A/L groups (Supplementary Table S6A).

Over the 13 weeks of the trial, the BP was autonomously dosing insulin a median of 96%–97% of the time, with CGM input available 90% of the time. While the BP was in use, median autonomous dosing was 97%–98%, with CGM input available for 90%–91% of the time (circumstances where iLet was not dosing insulin included empty insulin cartridge, battery discharged, infusion set occlusion, and insulin delivery paused such as for exercise).

In the SC group, CGM use was high, with median usage over the 13 weeks of the trial being 97% (IQR 95% , 98%). All but one participant used CGM at least 80% of the time (70% of the time in one participant, Supplementary Table S6B).

Efficacy outcomes

BP-F group versus SC group

In the primary analysis, mean HbA1c decreased from 7.8% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks in the BP-F group and from 7.6% ± 1.2% to 7.5% ± 0.9% in the SC group (adjusted difference in mean change in HbA1c = −0.5%, 95% CI −0.7 to −0.3, P < 0.001, Table 2 and Fig. 1). The treatment effect on HbA1c was evident in the first 6 weeks (Supplementary Fig. S2). Time <54 mg/dL over 13 weeks was noninferior in the BP-F group compared with the SC group (adjusted group difference 0.00%, 95% CI −0.07 to 0.05, P < 0.001 for non-inferiority, Table 2 and Fig. 2).

FIG. 1.

HbA1c at 13 Weeks. (A) Cumulative distribution of HbA1c at 13 weeks (N = 53 SC, 111 BP-F, 102 BP-A/L). (B) Scatterplot of HbA1c (%) at 13 weeks versus baseline (N = 52 SC, 111 BP-F, 102 BP-A/L). BP-A/L, BP with aspart or lispro; BP-F, BP with fast-acting insulin aspart; SC, standard care.

FIG. 2.

Time <54 mg/dL Outcome. (A) Boxplots of % time <54 mg/dL (N = 54 SC, 114 BP-F, 107 BP-A/L). Black dots indicate the mean values, horizontal bars in the boxes indicate the medians, and the bottom and top of each box represent the 25th and 75th percentiles, respectively. (B) Scatterplot of % time <54 mg/dL at 13 weeks versus baseline (N = 54 SC, 113 BP-F, 106 BP-A/L).

Analyses of the following five secondary outcomes in the prespecified hierarchical analysis plan also were statistically significant at P < 0.001 favoring the BP-F group compared with the SC group: mean CGM glucose, time in range 70–180 mg/dL (TIR), time >180 mg/dL, time >250 mg/dL, and glucose SD. Time <70 mg/dL was low at baseline and the treatment group difference at 13 weeks was not statistically significant (P = 0.54 for superiority).

Mean CGM glucose was decreased by 18 mg/dL on average in the BP-F group compared with the SC group (P < 0.001) over the 24 h of the day (Fig. 3A). Over 13 weeks, mean CGM glucose in the participants in the BP-F group was in a tight range irrespective of the baseline mean CGM glucose (Fig. 4). TIR was increased by 14% (3.4 h/day) on average in the BP-F group compared with the SC group (Table 2 and Fig. 5). It can be seen in Supplementary Table S7A and Supplementary Figure S3 that TIR increased in the first 4 weeks and then remained similar through 13 weeks.

FIG. 3.

Mean glucose by hour over the 24-h day. (A) BP-F group versus SC group. (B) BP-F group versus BP-A/L group. Dots and solid lines represent the medians, colored area reflects the interquartile range (extending to 25th and 75th percentiles), and dashed lines represent the 10th and 90th percentiles.

FIG. 4.

Scatterplot of mean glucose at 13 weeks versus baseline (N = 54 SC, 113 BP-F, 106 BP-A/L).

FIG. 5.

Time in range 70–180 mg/dL (N = 54 SC, 113 BP-F, 106 BP-A/L). (A) Cumulative distribution of % time 70–180 mg/dL at 13 weeks. (B) Scatterplot of % time in range 70–180 mg/dL at 13 weeks versus baseline.

Secondary HbA1c outcomes and other secondary CGM outcomes reflective of hyperglycemia all indicated a strong treatment benefit for the BP-F group compared with the SC group (Table 3 and Supplementary Tables S8 and S9). Although continuous CGM hypoglycemia outcomes did not show significant differences between the BP-F and SC groups, a higher proportion of the BP-F group met the targets of <4% time <70 mg/dL (96% vs. 80%, P = 0.003) and <1% time <54 mg/dL (96% vs. 81%, P < 0.001, Table 3).

Table 3.

Secondary Glycemic Outcomes

	SC group, N = 53	BP-F group, N = 111	BP-A/L group, N = 102	BP-F versus SC	BP-F versus BP-A/L
				13w adjusted risk difference (95% CI) [P]a
HbA1c
HbA1c <7.0%	15 (28%)	49 (44%)	43 (42%)	17% (6 to 28) [0.002]	4% (−10 to 20) [0.73]
HbA1c <7.5%	23 (43%)	86 (77%)	76 (75%)	35% (26 to 45) [<0.001]	5% (−12 to 24) [0.73]
HbA1c <8.0%	41 (77%)	105 (95%)	97 (95%)	17% (8 to 29) [0.001]	1% (−7 to 8) [0.90]
HbA1c improvement from baseline >0.5%	9 (17%)	62 (56%)	44 (43%)	35% (25 to 42) [<0.001]	7% (−4 to 17) [0.49]
HbA1c improvement from baseline >1.0%	2 (4%)	30 (27%)	23 (23%)	21% (7 to 27) [0.02]	2% (−7 to 12) [0.73]
HbA1c relative improvement from baseline >10%	2 (4%)	42 (38%)	32 (31%)	31% (23 to 37) [<0.001]	2% (−11 to 15) [0.90]
HbA1c improvement from baseline >1.0% or HbA1c <7.0%	16 (31%)	66 (59%)	58 (57%)	27% (14 to 40) [<0.001]	1% (−11 to 14) [0.90]

	N = 54	N = 113	N = 106
CGM metrics
% Time in range 70–180 mg/dL >70%	17 (31%)	65 (58%)	50 (47%)	26% (14 to 37) [<0.001]	13% (4 to 21) [0.01]
% Time in range 70–180 mg/dL improvement from baseline ≥5%	28 (52%)	90 (80%)	78 (74%)	29% (16 to 45) [<0.001]	3% (−7 to 12) [0.49]
% Time in range 70–180 mg/dL improvement from baseline ≥10%	24 (44%)	84 (74%)	72 (68%)	32% (21 to 46) [<0.001]	3% (−7 to 13) [0.50]
% Time <70 mg/dL <4%	43 (80%)	109 (96%)	93 (88%)	18% (9 to 26) [0.003]	8% (−1 to 14) [0.07]
% Time <54 mg/dL <1%	44 (81%)	108 (96%)	92 (87%)	15% (9 to 20) [<0.001]	8% (−2 to 16) [0.07]

Three BP-F, one SC, and five BP-A/L participants are missing week 13 HbA1c. One BP-F and one BP-A/L participant are missing CGM metrics during the 13-week follow-up period.

^a P-values are from a logistic regression model adjusting for the baseline version of the outcome and age at randomization as fixed effects and site as a random effect. A 95% confidence interval for the treatment group adjusted risk difference (BP-F minus SC and BP-F minus BP-A/L) was produced using parametric bootstrapping. Multiple comparisons were adjusted using the Benjamini-Hochberg adaptive false discovery rate correction procedure.

During both daytime and nighttime, there was substantial benefit favoring the BP-F group in increasing TIR and reducing time in hyperglycemia, with the beneficial effect appearing to be greater overnight than during daytime (Supplementary Table S10 and Supplementary Fig. S4). The frequency of time <54 mg/dL was low during both day and night (Supplementary Table S10 and Supplementary Fig. S5). Scatter plots comparing baseline to the 13-week follow-up period for time >250 mg/dL, time >180 mg/dL, time <70 mg/dL, and coefficient of variation are shown in Supplementary Figures S6–S9.

Results of per-protocol and sensitivity analyses were similar to the primary analysis (Supplementary Tables S11–S14). Analyses excluding prestudy HCL users (Supplementary Table S15) and analyses restricted to participants with baseline HbA1c >7.0% (Supplementary Table S16) demonstrated larger treatment effects, with adjusted mean treatment group differences of −0.7% (95% CI −0.9 to −0.4, P < 0.001) and −0.8% (95% CI −1.0 to −0.6, P < 0.001), respectively.

In subgroup analyses, the HbA1c and TIR benefits of BP-F compared with SC were evident across participant age range, for both higher and lower socioeconomic status, and for both MDI and pump (without automation) users (Supplementary Tables S17 and S18). A treatment effect on HbA1c was greater with higher baseline HbA1c, lower baseline TIR, and higher baseline time in hyperglycemia. There were no significant differences between the BP-F group and the SC group in total daily insulin dose, change in body weight, or body mass index (Supplementary Tables S19–S21).

BP-F group versus BP-A/L group

The decrease in HbA1c from baseline to 13 weeks was similar in the BP-F and BP-A/L groups: from 7.8% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks in the BP-F Group and from 7.6% ± 1.2% to 7.1% ± 1.0.6% in the BP-A/L group (adjusted difference in mean change in HbA1c = −0.0%, 95% CI −0.2 to 0.1, P = 0.67, Table 2 and Fig. 1). All secondary HbA1c outcomes also appeared similar between the two groups (Table 3).

Analyses of CGM metrics showed no significant difference between the BP-F and BP-A/L groups in mean CGM glucose (adjusted difference = −2.0 mg/dL, 95% CI −4.3 to 0.4, P = 0.10), but a 2% greater increase in TIR was observed with BP-F compared with BP-A/L (95% CI 1 to 4, P = 0.005; Table 2 and Fig. 5) related to less hyperglycemia (Table 2), which was reflected in a greater proportion of the BP-F group having TIR >70% (58% vs. 47%; adjusted difference = 13%, 95% CI 4 to 21, P = 0.01). However, the proportion of participants with TIR improvement of ≥5% was not significantly different between groups (80% vs. 74%, adjusted difference = 3%, 95% CI −7 to 12, P = 0.49, Table 3). Mean CGM glucose over the 24 h of the day appeared similar in the BP-F and BP-A/L groups (Fig. 3B). Hypoglycemic metrics were not significantly different comparing BP-F and BP-A/L (Tables 2 and 3).

Per-protocol analyses, sensitivity analyses, analyses excluding prestudy HCL users, and analyses restricted to participants with baseline HbA1c >7.0% produced similar results to the main analyses, with the BP-F and BP-A/L groups having similar HbA1c outcomes (Supplementary Tables 11–16). Subgroup analyses did not suggest the presence of any statistical interaction of baseline characteristics on treatment effect for outcomes of HbA1c, TIR, or mean CGM glucose.

There were no significant differences between the BP-F group and the BP-A/L group in total daily dose of insulin, change in body weight or body mass index (Supplementary Tables S19–S21). Patient-reported outcomes were similar comparing the BP-F and BP-A/L groups on nine surveys (Supplementary Table S22).

Adverse events and device issues

There were three severe hypoglycemia events in 3 participants in the BP-F group (2.6% of 114 participants), two events in 1 participant in the SC group (1.9% of 54 participants), and seven events in 7 participants in the BP-A/L group (6.5% of 107 participants). The rates of severe hypoglycemia were 10.2, 14.2, and 25.5 per 100 person-years, respectively (P = 0.83 comparing BP-F vs. SC and P = 0.20 comparing BP-F vs. BP-A/L). Two participants in the BP-F group each experienced one diabetic ketoacidosis event caused by an infusion set failure, and none in the BP-A/L or SC groups.

Among the other reportable adverse events in the BP groups, most were related to hyperglycemia with or without ketosis and were attributed to infusion set failure; there were 52 such events in the BP-F group and 34 such events in the BP-A/L group (Table 4). A summary of BP group device issues is provided in Supplementary Table S23.

Table 4.

Safety Outcomes During the 13-Week Trial Period

	SC group (N = 54)	BP-F group (N = 114)	BP-A/L (N = 107)	P-valuesa BP-F versus SC [BP-F vs. BP-A/L]
Event
Any adverse event
No. of patients [events]	5 [6]	59 [83]	43 [63]
Specific events
Severe hypoglycemia No. of patients (%) [No. of events]	1 (2) [2]	3 (3) [3]	7 (7) [7]	0.83 [0.20]
Incidence rate per 100 person-yearsb	14.2	10.2	25.5
Diabetic ketoacidosis No. of events	0	2	0
Other serious adverse events No. of patients (%) [No. of events]c	1 (2) [1]	0 (0) [0]	1 (<1) [1]
HbA1c worsening by ≥0.5%—No. of patients (%)	4 (8)	7 (6)	4 (4)	0.66 [0.15]
Other adverse events No. of patients (%) [No. of events]
Hyperglycemia with or without ketosis related to study deviced	NA	40 (35) [52]	27 (25) [34]
Hyperglycemia with or without ketosis not related to study device	0 (0) [0]	12 (11) [14]	12 (11) [13]
Nonsevere hypoglycemia	0 (0) [0]	0 (0) [0]	1 (<1) [1]
Other reportable adverse events	3 (6) [3]	10 (9) [12]	7 (7) [7]

^a P-values calculated only for the outcomes pre-specified in the Statistical Analyses Plan. P-value for number of severe hypoglycemia events per subject is produced from a Poisson regression model adjusting for prior hypoglycemia events, baseline age and central lab HbA1c at randomization as fixed effects and site as a random effect. P-value for proportion of participants with HbA1c worsening by ≥0.5% produced from a logistic regression model adjusting for age at randomization and central lab HbA1c at randomization as fixed effects with site as a random effect.

^b Severe hypoglycemia defined as cognitive impairment due to hypoglycemia that required the assistance of another individual to administer carbohydrate treatment.

^c Other SAEs. Hypoglycemia (1) in BP-A/L group. The hypoglycemic event did not meet criteria for severe hypoglycemia related to cognitive impairment but was considered a serious adverse event (significant medical event) as judged by the investigator. Epiglottitis (1) in SC group.

^d Seventy-eight events were related to infusion set issues, three due to CGM-to-iLet communication issues, one to a cartridge issue, one to pump leakage, one to pump shutdown, two to other pump problems.

Discussion

This multicenter, randomized controlled trial evaluated the insulin-only configuration of the BP using fast-acting insulin aspart in comparison with standard care (which included CGM for all participants) and with the BP using insulin aspart or insulin lispro. The study cohort comprised racially and socioeconomically diverse adults with T1D ranging in age from 18 to 83 years who in prestudy were using either an HCL system, a pump without automation with or without CGM, or MDI with or without CGM for insulin delivery, and had varying levels of glycemic control with baseline HbA1c values ranging from 5.3% to 14.9%.

In the main analyses, which compared the BP-F group with the SC group, a statistically significant and clinically meaningful 0.5% reduction in HbA1c was found with BP-F compared with SC without an increase in CGM-measured hypoglycemia, which was low at baseline and remained low over 13 weeks of the trial. There was also a statistically significant 14% increase in TIR, which equates with 3.4 h/day greater TIR on average, and a statistically significant 18 mg/dL decrease in mean CGM glucose, as well as statistically significant decreases in hyperglycemia. This increase in TIR and decrease in mean CGM glucose were seen as early as the first day of BP use, and after the first week, remained reasonably constant through the 13 weeks. Beneficial effects were seen during both daytime and nighttime. The glycemic benefits observed with BP-F versus SC are particularly impressive since 35% of the cohort was using an HCL system before the study and 32% had baseline HbA1c ≤7.0%, and as anticipated, these participants had little further improvement in HbA1c and CGM outcomes. The improvement in glycemic metrics occurred without an increase in the TDD of insulin.

The largest reduction in HbA1c occurred in participants who had the highest baseline HbA1c levels. This is an important finding, with the potential for substantial public health benefit, since these individuals are at greatest risk for developing chronic diabetic micro- and macrovascular complications.¹⁸ A beneficial treatment effect was consistently observed across a wide range of other baseline characteristics, including participants of racial/ethnic minority groups or lower socioeconomic status as well as in both MDI and pump users without automation.

Few randomized trials have assessed a closed-loop system for three or more months, and no trial of this duration used fast-acting insulin aspart in the system. The pivotal study of the HCL t:slim X2 insulin pump with Control-IQ Technology (Control-IQ; Tandem Diabetes Care), which included 168 individuals with T1D from 14 to 71 years in age with mean baseline HbA1c of 7.4%, found a 0.3% mean improvement in HbA1c and an 11% mean improvement in TIR compared with a control group using sensor-augmented pump therapy.⁴ A randomized trial evaluating the 670G HCL system (Medtronic Diabetes), which included 120 adults with T1D with mean baseline HbA1c of 7.4%, reported a 0.4% reduction in HbA1c and a 15% increase in TIR compared with a control group that did not use CGM or other HCL systems.¹⁹

Other randomized trials evaluating HCL systems not currently available in the United States include a 12-week trial with 86 children and adults with T1D 6 years and older²⁰ that reported an 11% improvement in TIR and 0.4% improvement in HbA1c compared with a control group using sensor-augmented pump (SAP); and a 12-week trial with 68 adults²¹ reported a 9% improvement in TIR and 0.2% improvement in HbA1c compared with a control group using SAP. The Medtronic 670G² and 780G⁵ pivotal trials and the Insulet Omnipod 5 pivotal trial³ did not include a control arm; thus, a direct comparison with our trial is not possible.

All these other HCL systems require information about the pre-HCL insulin regimen for initialization and require the user to routinely titrate insulin dosing and count carbohydrates, unlike the BP in this study, which is initialized only with body weight and does not require carbohydrate counting, setting or adjusting basal insulin, or manual correction boluses.

In our comparison of fast-acting insulin aspart with insulin aspart/lispro, no difference was observed in HbA1c outcomes or mean glucose. However, mean TIR was 2% higher with fast-acting insulin aspart than insulin aspart/insulin lispro, associated with an increase in the percentage of participants achieving TIR >70%. This slight increase in mean TIR was not associated with either a greater proportion of participants increasing TIR by ≥5%, an amount that has been considered to be clinically meaningful,²² or enhanced quality of life as assessed in multiple patient-reported outcome surveys.

The slightly higher TIR with fast-acting insulin aspart compared with insulin aspart or insulin lispro is similar to the finding of Lee et al.²³ In that crossover trial (6-week periods) of 25 adults with T1D using the Medtronic Advanced HCL system, mean TIR was 1.9% higher with fast-acting insulin aspart compared with insulin aspart. Most other studies comparing fast-acting insulin aspart with insulin aspart in closed-loop systems in adults with T1D have not demonstrated more than slight differences. In a crossover trial (8-week periods) of 25 adults with T1D using the Cambridge CamAPS FX closed loop system, there were no differences in TIR, mean CGM glucose, or hyperglycemia metrics; however, a slight, statistically significant reduction in hypoglycemia was observed.⁹ A crossover trial (two 2-week periods) of 19 adults comparing fast-acting insulin aspart versus insulin aspart in the 670G HCL system found a 3% improvement in TIR with fast-acting insulin aspart.¹¹

In this study, no differential information was provided to the BP about the absorption kinetics of fast-acting insulin aspart versus insulin aspart or insulin lispro and little difference was seen in efficacy outcomes. One crossover trial (2-week periods) in 18 adults with T1D¹⁹ evaluating the insulin-only configuration of the BP-F did show improvements in mean CGM glucose and TIR relative to the BP with insulin aspart when the insulin absorption parameter used by the BP algorithms was set to lower values with fast-acting insulin aspart than with the default value used with insulin aspart (which was the same default value used in this study in both the BP-F and BP-A/L groups).

It remains to be seen in larger studies if optimization of the insulin absorption parameter used by the BP algorithms with fast-acting insulin aspart might provide further benefits to glycemic control and CGM outcomes than those observed in this study.

There was no indication of a safety concern using fast-acting insulin aspart in the BP. The rate of severe hypoglycemia events in the BP-F group was comparable to that in the SC group and numerically lower than the rate in the BP-A/L group, although the difference was not statistically significant. There were two diabetic ketoacidosis (DKA) events in the BP-F group, both of which were attributed to infusion set failure.

The greater number of infusion set failures reported in the BP groups than in the SC group may be explained by differential adverse event reporting between the groups rather than the BP groups having a truly higher rate of infusion set failure than the SC group. According to the protocol, infusion set failures were only reportable adverse events in the BP groups. Therefore, none was reported in the SC group. In addition, the BP groups received specific written instructions on identifying and managing potential infusion set failures, which included contacting the clinical site, while the SC group was instructed to follow their routine diabetes management and contact their primary diabetes care provider with any concerns or questions.

Although only a single infusion set was available for use with the BP, it is one of the most commonly used commercially available infusion sets. If we assume that infusion sets were changed on average every 3 days, the 80 hyperglycemia-associated infusion set failures in the BP groups represent a failure rate of 1.2% for 6659 infusion sets. This frequency is lower than what would be expected from studies evaluating infusion set failure rate.^24–27 It is also noteworthy that there were significantly fewer episodes of prolonged hyperglycemia (defined as CGM glucose >300 mg/dL for at least 90 min during a 120-min period) with the BP than SC.

Strengths of the trial include the inclusion of individuals with T1D across a wide range of baseline characteristics, which enhances the generalizability of the results, a participant retention rate of 99%, high adherence to use of the assigned devices in both treatment groups, and the use of real-time CGM by all participants in the SC group in addition to their personal insulin delivery method, which included MDI users and insulin pump users with or without HCL control. Although the trial was conducted during the COVID pandemic, this did not adversely affect patient retention or protocol adherence.

The main limitation of the trial was that the low amount of baseline hypoglycemia precluded an evaluation as to whether the insulin-only BP system can reduce hypoglycemia, but it was clear from the results that it does not increase CGM-measured hypoglycemia. More unscheduled contacts occurred in the BP groups than the SC group, but this is inherent in the study design, in which one group uses an investigational device and the other group follows their usual care and contacts their own health care providers with questions.

In conclusion, the BP using fast-acting insulin aspart appears to be safe and substantially improves HbA1c and CGM metrics of TIR, mean CGM glucose, and hyperglycemia, without increasing CGM-measured hypoglycemia, in comparison with standard-care insulin delivery plus CGM. The benefit of the BP was observed in both younger and older adults of both higher and lower socioeconomic status who were using either MDI or an insulin pump therapy. However, use of fast-acting insulin aspart in the BP did not improve HbA1c outcomes, mean glucose, or patient-reported outcomes compared with use of insulin lispro or insulin aspart in the BP. Fast-acting insulin aspart did marginally increase mean TIR relative to insulin aspart or insulin lispro, but not the percentage of participants increasing TIR by ≥5%.

BP therapy is initialized by entering only the user's body weight, and as such, the BP differs from the current FDA-approved/cleared HCL systems in not requiring any quantitative information about the previous insulin regimen, or estimates of carbohydrates at mealtimes, or manually adjusting or titrating insulin doses. These features may facilitate adoption by a broad population of people with T1D and health care providers.

Author Disclosure Statement

Dr. Beck reports no personal financial disclosures but reports that his institution has received funding on his behalf as follows: grant funding and study supplies from Tandem Diabetes Care, Beta Bionics, and Dexcom; study supplies from Medtronic, Ascencia, and Roche; consulting fees and study supplies from Eli Lilly and Novo Nordisk; and consulting fees from Insulet, Bigfoot Biomedical, vTv Therapeutics, and Diasome.

Dr. Russell has issued patents and pending patents on aspects of the bionic pancreas that are assigned to Massachusetts General Hospital and licensed to Beta Bionics, has received honoraria and/or travel expenses for lectures from Novo Nordisk, Roche, and Ascensia, serves on the scientific advisory boards of Unomedical, served on scientific advisory board and had stock in Companion Medical that was bought out by Medtronic, has received consulting fees from Beta Bionics, Novo Nordisk, Senseonics, and Flexion Therapeutics, has received grant support from Zealand Pharma, Novo Nordisk, and Beta Bionics, and has received in-kind support in the form of technical support and/or donation of materials from Zealand Pharma, Ascencia, Senseonics, Adocia, and Tandem Diabetes.

Dr. Damiano has issued patents and pending patents on aspects of the bionic pancreas, and is an employee, the Executive Chair of the Board of Directors, and shareholder of Beta Bionics. Dr. El-Khatib has issued patents and pending patents on aspects of the bionic pancreas and is an employee and shareholder of Beta Bionics. Ms. Ruedy has no personal financial disclosures but reports that her employer has received grant support from Beta Bionics, Dexcom and Tandem Diabetes Care. Ms. Balliro reports receiving consulting payments from Beta Bionics, Novo Nordisk and Zealand Pharma. Ms. Li has no personal financial disclosures but reports that her employer has received grant support from Beta Bionics, Dexcom and Tandem Diabetes Care. Dr. Calhoun is a former Dexcom employee and his current employer has received consulting payments on his behalf from vTv Therapeutics, Beta Bionics, Dexcom, and Diasome.

Funding Information

Study funding was provided by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (Grant #1UC4DK108612-01), by an Investigator-Initiated Study award from Novo Nordisk, and by Beta Bionics, Inc., which also provided the experimental BP devices used in the study. Fast-acting insulin aspart and insulin aspart were provided by Novo Nordisk and insulin lispro was provided by Eli Lilly. Blood glucose meters and test strips (Contour^®Next One Blood Glucose Monitoring System) were provided by Ascensia Diabetes Care, Basel, CH. Continuous glucose monitor sensors and transmitters were purchased from Dexcom, Inc. at a discounted price.

Supplementary Material

Supplementary Appendix S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

Supplementary Table S6

Supplementary Table S7

Supplementary Table S8

Supplementary Table S9

Supplementary Table S10

Supplementary Table S11

Supplementary Table S12

Supplementary Table S13

Supplementary Table S14

Supplementary Table S15

Supplementary Table S16

Supplementary Table S17

Supplementary Table S18

Supplementary Table S19

Supplementary Table S20

Supplementary Table S21

Supplementary Table S22

Supplementary Table S23

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

Supplementary Figure S5

Supplementary Figure S6

Supplementary Figure S7

Supplementary Figure S8

Supplementary Figure S9