Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial

Question  Does once-daily oral verapamil preserve pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes?

Findings  In a randomized clinical trial including 88 children and adolescents with newly diagnosed type 1 diabetes, C-peptide levels (a measure of pancreatic beta cell function) measured during a mixed-meal tolerance test 52 weeks after diagnosis were 30% higher with verapamil compared with placebo. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% in the verapamil group vs 71% in the placebo group. Verapamil had few adverse events.

Meaning  Verapamil partially preserved stimulated C-peptide secretion at 52 weeks compared with placebo and was well tolerated in children and adolescents with newly diagnosed type 1 diabetes.

Importance  In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes.

Objective  To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes.

Design, Setting, and Participants  This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022.

Interventions  Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care.

Main Outcomes and Measures  The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes.

Results  Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A_1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, −0.3% [95% CI, −1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment.

Conclusions and Relevance  In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.

Trial Registration  ClinicalTrials.gov Identifier: NCT04233034

Type 1 diabetes, an autoimmune condition resulting in the destruction of insulin-producing pancreatic beta cells, affects more than 1 million people in the US.¹ Maintenance of even modest residual beta cell function, which is assessed by stimulated C-peptide secretion, is a desirable goal and is associated with lower risk of diabetes-related vascular complications and hypoglycemia.^2,3

Over the past 3 decades, a variety of approaches aimed at preserving C-peptide secretion after the diagnosis of type 1 diabetes have been tested. A small number of medications have shown efficacy in preserving C-peptide secretion in newly diagnosed patients with type 1 diabetes when tested in sufficiently powered randomized clinical trials.^4,5 Despite beneficial effects on beta cell function and insulin secretion, only 1 medication has advanced to approval by the US Food and Drug Administration, and thus far none has achieved widespread clinical implementation. Teplizumab was recently approved for the treatment of stage 2 type 1 diabetes (positive diabetes-related autoantibodies with evidence of dysglycemia), but not for the treatment of stage 3 type 1 diabetes (new-onset, clinically evident). To date, the majority of disease modification strategies for type 1 diabetes have focused on targeting immune responses.⁴

In recent years, a growing number of pathways intrinsic to the beta cell have been linked with type 1 diabetes pathophysiology. Thioredoxin-interacting protein overexpression has been shown to induce pancreatic beta cell apoptosis and be involved in glucotoxicity-induced beta cell death in culture and mouse models.⁶ Calcium channel blockers, such as verapamil, reduce thioredoxin-interacting protein expression and beta cell apoptosis^7-9 and may be beneficial in beta cell preservation after a type 1 diabetes diagnosis. In 2018, a placebo-controlled, pilot and feasibility randomized clinical trial was published¹⁰ that found a 35% relative increase in stimulated C-peptide levels after 12 months in 11 adults with newly diagnosed type 1 diabetes treated with oral verapamil compared with 13 adults taking placebo.

We conducted a double-blind, placebo-controlled randomized clinical trial of children and adolescents aged 7 years to 17 years with newly diagnosed stage 3 (clinically apparent) type 1 diabetes to assess the safety and efficacy of verapamil in preserving beta cell function 12 months after diagnosis.

The trial was conducted at 6 pediatric diabetes centers in the US. The trial protocol was approved by the Jaeb Center for Health Research institutional review board (the trial protocol and statistical analysis plan appear in Supplement 1). Written informed consent was obtained from a parent or legal guardian and assent was obtained from the participants (however, if they turned 18 years of age during the trial, the participants signed the informed consent form). An independent data and safety monitoring board provided trial oversight. The trial protocol included a factorial design and also evaluated the effect of intensive diabetes management using an automated insulin delivery system vs standard diabetes management on beta cell function, which is reported separately.¹¹

Eligible participants were aged 7 years to 17 years with type 1 diabetes diagnosed within 31 days of randomization, had at least 1 positive islet autoantibody, weighed 30 kg or greater, and had no contraindication to use of verapamil (complete inclusion and exclusion criteria appear in eTable 1 in Supplement 2 and an overview of the study procedures at the screening, randomization, and follow-up visits appears in eTable 2 in Supplement 2). The lower weight limit was due to verapamil dosing constraints.

Using a balanced factorial design (1:1:1:1), each participant was randomly assigned to the verapamil group or the placebo group and also to receive either intensive diabetes management with an automated insulin delivery system (from either Tandem Diabetes Care or Medtronic) or standard care diabetes management (Figure 1). Standard care diabetes management, which included use of a continuous glucose monitor (Dexcom G6), was determined by the participant and their health care provider. The computer-generated randomization schedule was stratified by site and used a permuted-block design.

An extended-release formulation of verapamil was used. The drug dose was dependent on each participant’s weight and was started with 60 mg/d or 120 mg/d. The dose was escalated at 2- to 4-week intervals to a maximum of dose of 360 mg/d for participants weighing more than 50 kg. The dose was held, decreased, or discontinued if adverse events occurred. Safety visits occurred approximately 1 week after initiation of the study drug and after each dose increase to measure blood pressure and pulse. Levels of liver enzymes (alanine transaminase and aspartate aminotransferase) were measured and an electrocardiogram was performed at screening and at the 6-week, 26-week, and 52-week visits. Adherence was assessed with pill counts based on the bottles dispensed and returned.

Participants completed a follow-up visit 6 weeks after randomization and then at 13, 26, 39, and 52 weeks from the time of type 1 diabetes diagnosis. At randomization and at most follow-up visits (except at 6 weeks), blood was drawn for central laboratory measurement of hemoglobin A_1c using the Tosoh G8 HPLC Analyzer and a 2-hour mixed-meal tolerance test was performed for central laboratory measurements of C-peptide levels using the Roche Cobas e801 unit.

Race and ethnicity information were collected to characterize the cohort. Race information was solicited from the participant in response to this question: “Which of the following racial designations best describes you?” The participant could select race from fixed categories, which allowed for the reporting of more than 1 race. Hispanic ethnicity information was solicited from the participant in response to this question: “Do you consider yourself to be Hispanic/Latino or not Hispanic/Latino?”

The primary outcome was area under the curve (AUC) values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. The secondary outcomes included (1) peak C-peptide level and the proportion with a peak C-peptide level of 0.2 pmol/mL or greater; (2) hemoglobin A_1c levels; and (3) the following glucose metrics measured with continuous glucose monitoring¹² during the 28 days prior to each visit: mean glucose concentration and percentage of time with glucose concentration in the range of 70 to 180 mg/dL or 70 to 140 mg/dL and percentage of time with a glucose concentration greater than 180 mg/dL, greater than 250 mg/dL, less than 70 mg/dL, or less than 54 mg/dL. The safety outcomes included severe hypoglycemia and diabetic ketoacidosis.

The sample size was calculated to be 98 participants to provide 90% power with a 2-sided type I error rate of 5% to detect a 52-week treatment difference in C-peptide AUC between the verapamil group and the placebo group, assuming the true relative between-group difference in the target population was 50% and a dropout rate of no more than 10% (additional information appears in the eStatistical Methods in Supplement 2). Recruitment was affected by the COVID-19 pandemic and was stopped after 88 participants were randomized, providing 88% statistical power with the lower than expected dropout rate of 5.7%. This recruitment 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 secondary analyses unless otherwise indicated. 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 the drug use indicator (verapamil or placebo), controlling for age, time from diagnosis to randomization, and assignment to intensive diabetes management or standard diabetes management. The backtransformation of the mean value, exp(y) − 1, was reported as the geometriclike mean. The primary outcome was tested for a possible device × drug interaction using the same model described above with the inclusion of a drug × type of diabetes management interaction term.

Missing data were handled using the direct likelihood method, which maximizes the likelihood function integrated over the possible values of the missing data. Additional sensitivity analyses handled missing data by using the multiple imputation method of Rubin,¹³ using multiple imputation with a pattern mixture model, and using 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 because of imbalances between the 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 verapamil group and in the placebo group who took at least 80% of the prescribed study drug (based on pill counts) and who did not have data missing for 52-week C-peptide level.

Except for the primary analysis, the P values were adjusted to control the false discovery rate using the 2-stage Benjamini-Hochberg procedure. A 2-tailed P = .05 was the threshold for statistical significance for all analyses. Additional details appear in the eStatistical Methods in Supplement 2. The analyses were performed using SAS version 9.4 (SAS Institute Inc).

Between July 20, 2020, and October 13, 2021, 88 participants were randomly assigned to the verapamil group (n = 47) or the placebo group (n = 41) (Figure 1). The ages of the participants ranged from 7.5 years to 17.9 years (mean age, 12.7 years [SD, 2.4 years]); 36 were female (47%). Of the 88 participants, 3 (3%) identified as Black or African American, 79 (90%) identified as White, and 4 (5%) identified as having multiple races. Fifteen participants (17%) identified as being of Hispanic ethnicity (Table 1). The mean time from type 1 diabetes diagnosis to randomization was 24 days (SD, 4 days).

Follow-up was completed on September 15, 2022. The trial was completed by 44 of the 47 participants (94%) in the verapamil group and 39 of the 41 participants (95%) in the placebo group. The reasons for trial discontinuation appear in eTable 3 in Supplement 2. Among the trial completers, the visit completion rate for the 5 follow-up visits was 96% in each group. The C-peptide results were missing for 1 participant in each group at baseline and for 4 participants in the verapamil group and 3 participants in the placebo group at 12 months. Intensive diabetes management with an automated insulin delivery system was provided to 22 participants (47%) in the verapamil group and 20 participants (49%) in the placebo group and standard diabetes care was provided to 25 (53%) and 21 (51%), respectively.

The mean starting drug dose was 1.7 mg/kg/d (SD, 0.3 mg/kg/d) in the verapamil group and 1.7 mg/kg/d (SD, 0.3 mg/kg/d) in the placebo group and the mean ending doses were 5.8 mg/kg/d (SD, 1.3 mg/kg/d) and 6.3 mg/kg/d (SD, 1.4 mg/kg/d), respectively. At randomization, 25 of 46 participants (54%) in the verapamil group and 26 of 40 participants (65%) in the placebo group were prescribed 60 mg/d, whereas 21 (46%) and 14 (35%), respectively, were prescribed 120 mg/d. At 52 weeks, 4 of 39 participants (10%) in the verapamil group were taking 120 mg/d, 13 (33%) were taking 240 mg/d, and 21 (54%) were taking 360 mg/d. At 52 weeks, 3 of 38 participants (8%) in the placebo group were taking 120 mg/d, 14 (37%) were taking 240 mg/d, and 20 (53%) were taking 360 mg/d.

In addition to the 5 participants who dropped out of the trial, the study drug was discontinued due to presumed adverse drug events by 3 participants in the verapamil group and by 1 participant in the placebo group and was discontinued for other reasons by 2 participants in the verapamil group (eTable 4 in Supplement 2). A permanent or temporary dose reduction due to a presumed adverse drug event was made for 3 participants in the verapamil group and 3 participants in the placebo group (eTable 4 in Supplement 2).

The median drug adherence from pill counts was 94% (IQR, 85%-98%) in the verapamil group and was 93% (IQR, 84%-99%) in the placebo group; 84% and 79% of participants, respectively, had a drug adherence level of 80% or greater.

In the verapamil group, the mean C-peptide AUC was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks from diagnosis compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group. The adjusted between-group treatment difference at 52 weeks was 0.14 pmol/mL (95% CI, 0.01 to 0.27 pmol/mL; P = .04), representing a 30% higher C-peptide level with verapamil than with placebo (Table 2 and Figure 2A). After increasing from baseline to 13 weeks in both groups, the mean C-peptide AUC declined in the placebo group, whereas the mean was stable in the verapamil group through 26 weeks and then declined (Table 2 and Figure 2B).

During the 52-week mixed-meal tolerance test, the mean peak C-peptide level was 0.83 pmol/mL (SD, 0.37 pmol/mL) in the verapamil group compared with 0.55 pmol/mL (SD, 0.34 pmol/mL) in the placebo group (Figure 2C). The 52-week peak C-peptide level was 0.2 pmol/mL or greater in 41 of 43 participants (95%) in the verapamil group compared with 27 of 38 participants (71%) in the placebo group (eTable 5 in Supplement 2).

In the per-protocol and sensitivity analyses, which included adjustment for baseline imbalances between groups in body mass index percentile and prepubertal status (Tanner stage 1), the results were consistent with the primary analysis (eTable 6 in Supplement 2). The results also appeared consistent among the subgroups (eFigure in Supplement 2). Assignment to intensive diabetes management vs standard diabetes management did not influence the primary outcome results. In the verapamil group, the mean C-peptide AUC was 0.64 pmol/mL (SD, 0.32 pmol/mL) in the participants who received intensive diabetes management compared with 0.65 pmol/mL (SD, 0.30 pmol/mL) in those who received standard diabetes management, and in the placebo group, the mean C-peptide AUC was 0.45 pmol/mL (SD, 0.31 pmol/mL) in the participants who received intensive diabetes management compared with 0.44 pmol/mL (SD, 0.29 pmol/mL) in those who received standard diabetes management (P = .19 for interaction).

Hemoglobin A_1c decreased in the verapamil group from 10.3% at baseline to 6.6% at 52 weeks and in the placebo group from 10.2% at baseline to 6.9% at 52 weeks (mean between-group difference, −0.3% [95% CI, −1.0% to 0.4%]; Table 2 and eTable 7 in Supplement 2). The mean percentage of time with glucose concentration (measured with continuous glucose monitoring) in the range of 70 mg/dL to 180 mg/dL at 52 weeks was 74% in the verapamil group compared with 70% in the placebo group (mean between-group difference, 2% [95% CI, −9% to 13%]; Table 2 and eTables 8 and 9 in Supplement 2). In the verapamil group, the total insulin dose was 0.74 units/kg/d at baseline and 0.65 units/kg/d at 52 weeks compared with 0.64 units/kg/d and 0.74 units/kg/d, respectively, in the placebo group (mean between-group difference at 52 weeks, −0.12 units/kg/d [95% CI −0.30 to 0.05 units/kg/d]).

Thirty-nine participants (83%) in the verapamil group experienced 134 adverse events and 30 participants (73%) in the placebo group experienced 91 adverse events (Table 3 and eTable 10 in Supplement 2). One event of severe hypoglycemia occurred in each group and 1 event of diabetic ketoacidosis occurred in the placebo group. Three participants in each group experienced other serious adverse events that were not considered related to treatment.

Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group experienced a nonserious adverse event considered to be related to treatment. In the verapamil group, 3 participants experienced electrocardiogram abnormalities (prolonged PR interval in 1 participant, second-degree heart block and prolonged PR interval in 1 participant, and first-degree heart block in 1 participant) and 1 participant experienced hypotension. In the placebo group, 1 participant experienced bradycardia (Table 3). Mean blood pressure and mean heart rate collected at each visit did not show appreciable differences between groups (eTable 11 in Supplement 2).

Once-daily oral verapamil started within 31 days after diagnosis of type 1 diabetes slowed beta cell decline over 52 weeks in children and adolescents aged 7 years to 17 years. The natural history of type 1 diabetes involves a slight improvement in C-peptide secretion immediately after diagnosis and initiation of insulin therapy, followed by progressive C-peptide decline related to autoimmune beta cell destruction.^14,15 An initial improvement in stimulated C-peptide secretion was observed in both groups, but the verapamil group experienced a longer period of stability compared with the placebo group before C-peptide levels began to decline. In view of the favorable safety profile compared with immunosuppressive agents, once-daily oral administration, and low cost, initiation of verapamil therapy could be considered for patients with newly diagnosed type 1 diabetes.

The current randomized clinical trial confirms the findings of the pilot trial by Ovalle et al¹⁰ in adults with newly diagnosed type 1 diabetes. That study found a relative difference in mean C-peptide AUC of 35% after 12 months comparing 11 participants treated with verapamil vs 14 participants treated with placebo, similar to the finding of a 30% relative difference in the current pediatric and adolescent population. Further follow-up of the adult participants in the pilot study suggested a possible sustained benefit of verapamil at 2 years, although treatment during year 2 was not controlled.¹⁶

The 30% 1-year improvement in C-peptide secretion with verapamil is in the midrange of improvement reported for immunosuppressive agents that have been evaluated for newly diagnosed type 1 diabetes in randomized clinical trials.^4,17,18 However, it is difficult to compare treatment effects across studies due to lack of precision in the point estimates and differences in the study designs and characteristics of the enrolled cohorts. These immunosuppressive therapies are most effective shortly after the diagnosis of type 1 diabetes, with differences in C-peptide outcomes between treated and control participants becoming established within 6 months followed by a subsequent decline in C-peptide secretion similar to what was observed in the current trial with verapamil. Two years of treatment with abatacept,^19,20 1 year with golimumab,^5,21 2 annual courses with teplizumab,¹⁸ and single-course treatment with rituximab^22,23 and antithymocyte globulin^4,17 all demonstrated this pattern. The C-peptide benefits that persisted, sometimes for years, were due to early gains. There was minimal evidence that longer therapy added benefit. Whether the same is true for verapamil, an agent proposed to act via mechanisms that are not immunomediating, is unknown.

Significant differences in C-peptide secretion were not accompanied by meaningful treatment group differences in hemoglobin A_1c levels, continuous glucose monitoring parameters, or insulin dose. Glycemic control in the placebo group was very good, which may be reflective of the use of either an automated insulin delivery system or continuous glucose monitoring for diabetes management plus the presence of the honeymoon phase during the first year after type 1 diabetes diagnosis in which most patients have some residual beta cell function present. This presumption is supported by the finding that 71% of the placebo group had a peak C-peptide level of 0.2 pmol/mL or greater 52 weeks after diagnosis even though this percentage was less than the 95% of the verapamil group with a peak C-peptide level of 0.2 pmol/mL or greater. There was no effect of the factorial design randomization on either the intensive diabetes management groups (plus verapamil or placebo) or the standard diabetes management groups on the treatment group comparison of C-peptide levels.

We observed few treatment-related adverse events, none of which were serious, which is consistent with the known safety profile of verapamil.^24,25 It should be noted that drug therapy was approached cautiously because of our lack of experience in using verapamil in children with gradual weight- and symptom-based dose escalation over 2 months and close monitoring for bradycardia, hypotension, electrocardiogram changes, and liver function.

The strengths of this trial include the multicenter, double-blind, randomized design; the investigation of a drug with a mechanism of action distinct from immunotherapies; use of a drug with a prior safety profile in other populations; inclusion of a cohort confined to children and adolescents; the ethnic diversity of the participants; and the initiation of therapy within 31 days of diagnosis with type 1 diabetes.

This trial had limitations. First, the trial only included children who weighed 30 kg or greater due to the commercially available dosing options for extended-release verapamil. Second, due to the challenges surrounding the enrollment of participants during the COVID-19 pandemic in early 2020, we did not reach our original enrollment target. Third, the sample size was small for assessing adverse events of treatment.

In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.

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

Accepted for Publication: February 7, 2023.

Published Online: February 24, 2023. doi:10.1001/jama.2023.2064

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 Forlenza and McVean contributed equally to this article.

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

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

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

Critical revision of the manuscript for important intellectual content: Forlenza, McVean, 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: Forlenza, McVean, Beck, Bauza, DiMeglio, Clements, Neyman, Evans-Molina, Sims, Messer, Ekhlaspour, Rojas, Beasley, DuBose.

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

Conflict of Interest Disclosures: 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 McVean reported being an employee of Medtronic. Dr Beck reported that 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, Ascensia, 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, ProventionBio, and Zealand Pharma and study supplies from Dexcom. Dr Sherr reported receiving speaker 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 consulting 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 receiving 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 Care; 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 Funder/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 the 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.