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QuestionÌý Does near normalization of glucose levels preserve pancreatic beta cell function in youth with newly diagnosed type 1 diabetes?

FindingsÌý In a randomized clinical trial including 113 youths aged 7 to 17 years with newly diagnosed type 1 diabetes, there was no significant difference in C-peptide levels measured during a mixed-meal tolerance test (a measure of pancreatic beta cell function) 52 weeks after diagnosis between intensive management and standard care groups. Mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% with intensive management, which included automated insulin delivery, compared with 64% with standard care.

MeaningÌý Intensive diabetes management with automated insulin delivery did not affect the decline in pancreatic C-peptide secretion at 52 weeks in youths with newly diagnosed type 1 diabetes.

ImportanceÌý Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals.

ObjectiveÌý To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes.

Design, Setting, and ParticipantsÌý This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years.

InterventionsÌý Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo.

Main Outcomes and MeasuresÌý The primary outcome was mixed-meal tolerance test–stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis.

ResultsÌý Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, −0.01 [95% CI, −0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group.

Conclusions and RelevanceÌý In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks.

Trial RegistrationÌý ClinicalTrials.gov Identifier:

Despite advances in technology, youths with type 1 diabetes continue to struggle to meet glycemic targets, with less than 30% achieving the American Diabetes Association goal of a hemoglobin A_1c (HbA_1c) level less than 7%, and consequently most are at risk for vascular complications.¹ Residual pancreatic beta cell function, measured as stimulated C-peptide secretion, is associated with a reduced risk of long-term complications.² Methods to preserve beta cell function in newly diagnosed type 1 diabetes have been sought due to their potential long-term clinical benefit.²

It has been postulated that near normalization of glucose levels beginning shortly after diagnosis of type 1 diabetes could help preserve beta cell function by reducing glucotoxicity, which has been shown in rodent models to adversely affect beta cells.^3,4 One human trial has provided support for the glucotoxicity theory.⁵ Recent advances in automated insulin delivery systems enabling improved glycemia^6-8 provide the opportunity to test the hypothesis. After this current trial ended, Boughton et al⁹ reported no difference in C-peptide levels at 12 months comparing an intervention group using an automated insulin delivery system vs a control group. However, the intervention group only achieved a mean time in the target range of 70 to 180 mg/dL of 64% at 12 months (vs 54% in the control group). Because glucose levels were greater than 180 mg/dL for 7 hours per day, this trial was not an optimal test of the glucotoxicity theory.

The current randomized trial of youths aged 7 to 17 years with newly diagnosed stage 3 (clinically apparent) type 1 diabetes assessed the effect of intensive diabetes management, which included use of an automated insulin delivery system, on preservation of beta cell function 52 weeks after diagnosis.

The CLVer (Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New Onset Type 1 Diabetes) trial was conducted at 6 pediatric diabetes centers in the US. The protocol, which is available in Supplement 1, was approved by the Jaeb Center for Health Research institutional review board. Written informed consent was obtained from a parent or legal guardian and assent from participants, who signed the informed consent form if they turned 18 years during the trial. An investigational device exemption was approved by the US Food and Drug Administration for use of the automated insulin delivery systems. An independent data and safety monitoring board provided trial oversight. The protocol included a factorial design in which the effect of verapamil vs placebo on beta cell function was also evaluated; the results of which are reported separately.¹⁰

Eligible participants were 7 to 17 years old with type 1 diabetes diagnosed within 31 days of randomization and at least 1 positive islet autoantibody. Complete criteria are in eTable 1 in Supplement 2 and the screening testing is described in eTable 2 in Supplement 2.

Participants weighing less than 30 kg were randomly assigned in a 2:1 ratio to intensive diabetes management with an automated insulin delivery system or standard care diabetes management. Participants weighing 30 kg or more were randomly assigned in a balanced factorial design to the intensive management group or standard care group and to receive either oral verapamil or placebo. The weight limitation for the verapamil group of the trial was due to drug dosing constraints. The randomization schedule was computer-generated and stratified by site with a permuted-block design.

Participants assigned to intensive management were provided with 1 of 2 automated insulin delivery systems assigned 1:1 through randomization: either the Tandem t:slim X2 insulin pump with Control-IQ technology and Dexcom G6 sensor or the Medtronic MiniMed 670G 4.0 advanced hybrid closed-loop system with Guardian Sensor 3 prior to August 2021 or subsequently the MiniMed 780G system with Guardian Sensor 4. After initial device training, intensive management included frequent contacts by study staff (every 1-3 days for the first 2 weeks, at least twice a week for the second 2 weeks, and then every 1-2 weeks for the duration of the 52 weeks) plus nutrition management and 24-hour-a-day availability for participant contact, with the goal of near normalization of glucose concentrations by maximizing time in the target range of 70 to 180 mg/dL.

Participants assigned to the standard care group were given a Dexcom G6 continuous glucose monitor and received diabetes management from their personal health care team. Insulin delivery included multiple daily injections or an insulin pump with or without predictive low glucose suspend (closed-loop technology was not allowed).

Participants completed a visit 6 weeks after randomization and then at 13, 26, 39, and 52 weeks timed from type 1 diabetes diagnosis. At randomization and at each visit except 6 weeks, blood was drawn for central laboratory measurement of HbA_1c using the Tosoh G8 HPLC Analyzer and a 2-hour mixed-meal tolerance test was performed for central laboratory measurements of C-peptide using the Roche Cobas e801 unit.

The primary efficacy outcome was C-peptide area under the curve (AUC) during the mixed-meal tolerance test at 52 weeks. Secondary efficacy outcomes included peak C-peptide level and the proportion with peak C-peptide levels of 0.2 pmol/mL or greater. Glucose exposure was assessed by measurement of HbA_1c and by computing glucose metrics measured with continuous glucose monitoring during the 28 days prior to each visit (baseline continuous glucose monitoring data were not collected to minimize the time between type 1 diabetes diagnosis and randomization): mean glucose concentration and percentage of time in the following ranges: 70 to 180 mg/dL, 70 to 140 mg/dL, greater than 140 mg/dL, greater than 180 mg/dL, greater than 250 mg/dL, less than 70 mg/dL, and less than 54 mg/dL.¹¹ Safety outcomes included severe hypoglycemia and diabetic ketoacidosis.

Sample size was projected to be 131 participants with approximately 71 assigned to the intensive management group and 60 to the standard care group. With this sample size and assuming no more than a 10% dropout rate and an SD of 0.18 for the C-peptide AUC, statistical power was 96% to detect a difference between groups for a 50% relative treatment effect for the primary outcome. Recruitment was impacted by the COVID-19 pandemic and was stopped after 113 participants underwent randomization, which provided 94.8% statistical power considering the dropout rate of only 4.4%. This decision was related to funding considerations and was made without knowledge of the treatment effect.

Participants were analyzed in the group to which they were assigned by randomization regardless of the actual treatment received. All participants were included in the primary and all secondary analyses unless otherwise noted. Treatment group comparisons for the primary C-peptide outcome included all randomized participants with at least 1 analyzable C-peptide AUC value (at baseline or follow-up) and were made with a constrained longitudinal analysis by fitting the log(AUC+1) for each mixed-meal tolerance test as the outcome and testing for intensive vs standard diabetes management, controlling for age, time from diagnosis to randomization, and verapamil use. The back transform of the mean value, exp(y)-1, was reported as the geometric-like mean. The primary outcome was tested for a possible device-by-drug interaction using the same model described above with the inclusion of a drug by type of diabetes management interaction term.

Missing data were handled using direct likelihood, which maximizes the likelihood function integrated over possible values of the missing data. Additional sensitivity analyses handled missing data by Rubin multiple imputation, multiple imputation with a pattern mixture model, and available cases only. Another sensitivity analysis was performed that included Tanner stage and body mass index percentile as covariates in the model assessing the primary outcome due to imbalances between treatment groups at randomization. A per-protocol analysis was performed using the same method as the primary analysis in which the analysis cohort was restricted to participants in the intensive management and standard care groups who had nonmissing 52-week C-peptide data and participants in the intensive management group who used the closed-loop system at least 85% of the time.

P values were 2-tailed. Except for the primary analysis, P values were adjusted to control the false discovery rate using the 2-stage Benjamini-Hochberg procedure. A P value of .05 was the threshold for statistical significance for all analyses. Additional statistical methods are in eMethods in Supplement 2. Analyses were performed using SAS version 9.4 (SAS Institute).

Between July 20, 2020, and October 13, 2021, 113 participants were randomly assigned to the intensive management (n = 61) or standard care (n = 52) groups (Figure 1). Participant age ranged from 7.0 to 17.9 years (mean [SD], 11.8 [2.8] years); 4 participants (5%) identified as Black, 101 (89%) as White, and 6 (5%) as another or more than 1 race or ethnic group (Table 1). Sixteen participants (14%) identified as being of Hispanic ethnicity. Information on race and ethnicity was collected to characterize the cohort; participants identified their race and ethnicity through fixed categories.

A total of 88 participants also participated in the verapamil vs placebo comparison of the trial, with verapamil being received by 22 participants in the intensive management group and 25 in the standard care group. The mean (SD) time from type 1 diabetes diagnosis to randomization was 24 (5) days.

Follow-up was completed on September 15, 2022. The trial was completed by 60 of the 61 participants (98%) in the intensive management group and by 48 of the 52 participants (92%) in the standard care group. Reasons for discontinuation are provided in eTable 3 in Supplement 2. Among the trial completers, the visit completion rate for the 5 protocol follow-up visits was 99% in the intensive management group and 94% in the standard care group. C-peptide results were missing for 1 participant in each group at baseline and for 2 participants in the intensive management group and 6 participants in the standard care group at 12 months.

In the intensive management group, in addition to 1 participant who dropped from the trial, 1 participant permanently discontinued use of automated insulin delivery prior to their 39-week visit but continued to use the continuous glucose monitor through 52 weeks. Among the remaining 59 participants using automated insulin delivery at 52 weeks, the median time that closed loop was active over the entire study period was 93% (IQR, 86%-95%). Intensive management included a median of 35 contacts or visits (IQR, 27-48) in addition to the 5 protocol follow-up visits completed by both groups.

In the standard care group, 27 (56%) of the 48 participants completing the trial were using an insulin pump, 1 of which was part of an automated insulin delivery system prescribed by the health care professional, and 21 (44%) were using multiple daily injections at 52 weeks. Their median continuous glucose monitor use during the trial was 96% (IQR, 92%-97%).

Total daily insulin dose was 0.68 units/kg at baseline and 0.74 units/kg at 52 weeks in the intensive management group and 0.66 and 0.64 units/kg, respectively, in the standard care group (mean difference, 0.09 [95% CI, −0.01 to 0.20]; P = .07).

The mean C-peptide AUC decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks from diagnosis in the intensive management group and from 0.60 pmol/mL to 0.50 pmol/mL at 52 weeks in the standard care group (adjusted difference at 52 weeks, −0.01 [95% CI, −0.11 to 0.10]; P = .89; Table 2, Figure 2A). Both groups showed an increase in mean C-peptide AUC from baseline to 13 weeks followed by a decline thereafter (Figure 2B).

The mean (SD) peak C-peptide level at the 52-week visit was 0.56 (0.36) pmol/mL in the intensive management group and 0.62 (0.37) pmol/mL in the standard care group (Figure 2C). The 52-week C-peptide level was 0.2 pmol/mL or greater for 45 of 59 participants (76%) in the intensive management group vs 36 of 46 participants (78%) in the standard care group (eTable 4 in Supplement 2). Per-protocol and sensitivity analyses provided results consistent with the primary analysis (eTable 5 in Supplement 2). Results also appeared consistent in subgroups (eFigure in Supplement 2).

There was no interaction between intensive management and verapamil on C-peptide preservation. Among participants who received verapamil as part of the factorial design and had 52-week C-peptide results, the mean 52-week C-peptide AUC was 0.64 (0.32) pmol/mL in the 21 participants in the intensive management group and 0.65 (0.30) pmol/mL in the 22 participants in the standard care group. Among the participants who received placebo, the C-peptide AUC was 0.45 (0.31) pmol/mL in the 20 participants in the intensive management group and 0.44 (0.29) pmol/mL in the 18 participants in the standard care group (P value for interaction = .19).

Differences in glycemic exposure were observed between the 2 groups. The HbA_1c level decreased from 10.3% at baseline to 6.5% at 52 weeks in the intensive management group and from 10.2% to 7.1% in the standard care group (adjusted difference, −0.7% [95% CI, −1.1% to −0.3%]); 42 participants (71%) in the intensive management group and 26 (54%) in the standard care group had an HbA_1c level less than 7.0% at 52 weeks (Table 2; eTable 6 in Supplement 2). The mean time in the target range of 70 to 180 mg/dL was 82% in the intensive management group and 73% in the standard care group, averaged over the 5 periods of continuous glucose monitor data collection (Figure 2D; eTable 7 in Supplement 2), with 89% vs 71%, respectively, achieving time in the target range of 70% or greater; 62% vs 39% achieving time in the target range of 80% or greater; and 21% vs 18% achieving time in the target range of 90% or greater. At 52 weeks, time in the target range of 70 to 180 mg/dL was 78% in the intensive management group and 64% in the standard care group (adjusted difference, 16% [95% CI, 10%-22%]) (Table 2). Hyperglycemic metrics showed similar treatment group differences (Table 2; eTable 7 in Supplement 2).

There were 81 participants who received either verapamil or placebo as part of the factorial design and had 52-week continuous glucose monitor data. Among participants who received verapamil, the mean (SD) 52-week time in the target range of 70 to 180 mg/dL was 82% (11%) in the 21 participants in the intensive management group and 66% (19%) in the 23 participants in the standard care group. Among participants who received placebo, the mean (SD) time in the target range of 70 to 180 mg/dL was 76% (13%) in the 19 participants in the intensive management group and 63% (26%) in the 18 participants in the standard care group.

One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group (Table 3). There were 7 device-related adverse events in the intensive management group: 6 cases of hyperglycemia due to infusion set failure and 1 case of skin infection at the infusion site. The mean (SD) body mass index percentile at 52 weeks was 60 (29) in the intensive management group and 60 (28) in the standard care group.

In this multicenter randomized trial involving youths with newly diagnosed type 1 diabetes, no difference was observed in stimulated C-peptide secretion between the intensive management and standard care groups, despite a difference in metabolic control. Stimulated C-peptide levels initially increased between baseline and 13 weeks after diagnosis in both groups and then declined in both over the next 9 months. This pattern and the 52-week C-peptide levels are consistent with the natural history of C-peptide levels in the first year after diagnosis.^12,13 Glycemic improvement was safely achieved during the first year following diagnosis using an intensive management approach, which included use of an automated insulin delivery system and frequent contact with study clinicians to adjust diabetes management. The intensive approach resulted in an increase in mean time in the target glucose range of 70 to 180 mg/dL, measured with a continuous glucose monitor, of 3.8 hours per day compared with standard care, which included use of a continuous glucose monitor. Among the participants who weighed 30 kg or more and were part of the factorial design analysis, there was no indication of an interaction with verapamil. These findings demonstrate that improvement in hyperglycemia to the degree that is feasible with current technology and insulin formulations, combined with an intensive diabetes management approach, is not a successful intervention for beta cell preservation in children and adolescents with newly diagnosed type 1 diabetes.

The theory that glucose toxicity contributes to beta cell damage gained interest after the publication of a study by Shah et al⁵ in 1989. In that study, preservation of beta cell function 1 year after diagnosis was achieved in 12 adolescents compared with 14 control participants. This occurred after complete normalization of glucose levels for 2 weeks shortly after diagnosis using a Biostator in an inpatient setting with a target glucose of 60 to 80 mg/dL to achieve beta cell rest. Subsequently, Buckingham et al¹² did not demonstrate preservation of beta cell function using an early-generation automated insulin delivery system initiated within 7 days of diagnosis of type 1 diabetes in an inpatient setting for 3 days followed by outpatient sensor-augmented insulin pump therapy through 12 months. However, a treatment group glycemic difference was not achieved at 1 year; mean time in the target glucose range of 70 to 180 mg/dL was 69% with intensive management compared with 70% in the usual care control group.

In a recently published trial of 97 participants 10 to younger than 17 years old with type 1 diabetes diagnosed within the prior 21 days, Boughton et al⁹ found no difference in C-peptide AUC comparing an intervention group using an automated insulin delivery system vs a control group at 12 or 24 months. The intervention group achieved a mean time in the target glucose range of 70 to 180 mg/dL of 64% compared with 54% in the control group at 12 months. A higher time in the target range of 70 to 180 mg/dL of 82% over the course of the trial and 78% at 12 months with intensive management were achieved. The greater time in range in this trial compared with that in the Boughton et al⁹ trial likely reflects a higher percentage of time that the automated insulin delivery systems in this study were actively automating insulin delivery (93% through 12 months in the current trial vs 76% through 24 months in the Boughton et al⁹ trial) and this intensive approach to diabetes management with more frequent contacts with participants.

This intensive approach to management was an attempt to achieve as close to normal glycemia as is currently possible to test the hypothesis that normalization of glucose levels beginning shortly after diagnosis can preserve beta cell function. It was not intended to specifically test automated insulin delivery system use as it might be managed in a typical clinical practice; real-world implementation of this intensity of contact might be difficult. The mean HbA_1c level of 6.5% and time in range of 78% at 52 weeks from diagnosis likely represent the best glucose control that is possible with current technology and insulins but does not equate with the short-term beta cell rest achieved with the Biostator by Shah et al.⁵

The strengths of this trial include the multicenter randomized design with randomization within 31 days of diagnosis, an ethnically diverse study population, and a high participant retention rate. While the level of glycemia that was achieved did not preserve beta cell function, the treatment group differences in HbA_1c levels and glycemic metrics measured with continuous glucose monitoring were large. This degree of treatment effect, if sustained long-term, would be expected to have benefit in reducing the risk of vascular complications.¹⁴

Despite an attempt to achieve as near-normal glycemia as possible, there was still clinically significant hyperglycemia. Although the percentage of time in range achieved in this trial was higher than in prior trials, glucose levels nevertheless were greater than 180 mg/dL for about 5 hours per day. Two different types of continuous glucose monitor sensors were used in the trial, but there is no indication that this biased the results and the continuous glucose monitor results are consistent with the HbA_1c results.

In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks.

Corresponding Author: Roy Beck, MD, PhD, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (rbeck@jaeb.org).

Accepted for Publication: January 7, 2023.

Published Online: February 24, 2023. doi:10.1001/jama.2023.2063

Author Contributions: Dr Beck had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs McVean and Forlenza contributed equally to this article.

Concept and design: McVean, Forlenza, Beck, DiMeglio, Sherr, Clements, Neyman, Evans-Molina, Sims, Messer, DuBose, Kollman, Moran.

Acquisition, analysis, or interpretation of data: McVean, Forlenza, Beck, Bauza, Bailey, Buckingham, DiMeglio, Sherr, Clements, Evans-Molina, Messer, Ekhlaspour, McDonough, Van Name, Rojas, Beasley, DuBose, Kollman, Moran.

Drafting of the manuscript: McVean, Forlenza, Beck, Bauza, Bailey, Rojas, Moran.

Critical revision of the manuscript for important intellectual content: McVean, Forlenza, Bauza, Buckingham, DiMeglio, Sherr, Clements, Neyman, Evans-Molina, Sims, Messer, Ekhlaspour, McDonough, Van Name, Beasley, DuBose, Kollman, Moran.

Statistical analysis: Bailey, Kollman.

Obtained funding: McVean, Sherr, Moran.

Administrative, technical, or material support: McVean, Forlenza, Beck, Bauza, DiMeglio, Clements, Neyman, Evans-Molina, Sims, Messer, Ekhlaspour, Rojas, Beasley, DuBose.

Supervision: McVean, Forlenza, Beck, Bauza, Buckingham, Sherr, Clements, Neyman, Ekhlaspour, Van Name, DuBose, Kollman, Moran.

Conflict of Interest Disclosures: Dr McVean reported being an employee of Medtronic. Dr Forlenza reported serving as a consultant, speaker, or advisory board member for Medtronic, Dexcom, Abbott, Tandem Diabetes Care, Insulet, Lilly, and Beta Bionics and reported that his institution has received funding on his behalf for research grants from Medtronic, Dexcom, Abbott, Tandem Diabetes Care, Insulet, Lilly, and Beta Bionics. Dr Beck reported his institution has received funding on his behalf as follows: grant funding and study supplies from Tandem Diabetes Care, Beta Bionics, and Dexcom; grant funding from Bigfoot Biomedical; study supplies from Medtronic, Ascencia, and Roche; consulting fees and study supplies from Lilly and Novo Nordisk; and consulting fees from Insulet and Zucara Therapeutics. Dr Buckingham reported receiving grants, personal fees, and/or nonfinancial support from Medtronic, Tandem Diabetes Care, Insulet, Novo Nordisk, and Lilly and reported his institution has received research funding from Medtronic, Tandem Diabetes Care, Beta Bionics, and Insulet. Dr DiMeglio reported receiving consulting or advisory fees from Abata Therapeutics, MannKind, Provention Bio, and Zealand Pharma and study supplies from Dexcom. Dr Sherr reported receiving speaking honoraria from Lilly, Insulet, Medtronic, and Zealand Pharma; serving on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, Medtronic Diabetes, JDRF (formerly the Juvenile Diabetes Research Foundation) T1D Fund, StartUp Health T1D Moonshot, and Vertex Pharmaceuticals; receiving consultant fees from Insulet and Medtronic; and reported that her institution has received research grant support from Medtronic and Insulet. Dr Clements reported receiving personal fees from Glooko Inc and nonfinancial support from Dexcom and Abbott Diabetes Care. Dr Evans-Molina reported serving on advisory boards for ProventionBio, Isla Technologies, MaiCell Therapeutics, Avotres Inc, DiogenX, and Neurodon; receiving in-kind research support from Bristol Myers Squibb and Nimbus Therapeutics; receiving investigator-initiated grants from Lilly and Astellas Pharma; and having a patent for extracellular vesicle RNA cargo as a biomarker of hyperglycemia and type 1 diabetes and a provisional patent for a biomarker of type 1 diabetes (PDIA1 as a biomarker of beta cell stress). Dr Sims reported receiving compensation for educational lectures on type 1 diabetes screening from Medscape and the American Diabetes Association. Dr Messer reported receiving speaking or consulting fees from Dexcom, Tandem Diabetes Care, Capillary Biomedical (now owned by Tandem Diabetes Care), and Lilly; receiving grants from Insulet, Beta Bionics, and Tandem Diabetes; and being a current employee of Tandem Diabetes Care. Dr Ekhlaspour reported receiving consulting fees from Tandem Diabetes Care and Ypsomed Holding AG; receiving speaking fees from Insulet; and receiving research support from Medtronic and MannKind. Dr Van Name reported receiving research support from ProventionBio. Dr Kollman reported receiving grants from Dexcom and Tandem Diabetes Care. Dr Moran reported serving on advisory boards for Dompé Farmaceutici SpA, ProventionBio, and Abata Therapeutics; serving on a data and safety monitoring board for Novo Nordisk; and reported that her institution has received grant funding on her behalf from Abbott Diabetes, ProventionBio, Intrexon (now Precigen), and Caladrius Biosciences and study supplies from Novo Nordisk, Medtronic, and Abbott Diabetes. No other disclosures were reported.

Funding/Support: This trial was funded by JDRF (formerly the Juvenile Diabetes Research Foundation). Medtronic, Tandem Diabetes Care, and Dexcom provided the devices used in the trial.

Role of the Funders/Sponsor: Representatives of JDRF participated in initial discussions regarding protocol development but had no role in the conduct of the trial, data collection or analysis, or preparation of the manuscript. Medtronic, Tandem Diabetes Care, and Dexcom reviewed the manuscript but were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the CLVer Study Group appear in Supplement 3. A list of the study center staff and other individuals who participated in the conduct of the trial appears in Supplement 2.

Meeting Presentation: This article was presented at the 16th International Conference on Advanced Technologies & Treatments for Diabetes; February 24, 2023; Berlin, Germany.

Data Sharing Statement: See Supplement 4.