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Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes.

ABSTRACT: Preservation of β-cell function as measured by stimulated C-peptide has recently been accepted as a therapeutic target for subjects with newly diagnosed type 1 diabetes. In recently completed studies conducted by the Type 1 Diabetes Trial Network (TrialNet), repeated 2-hour Mixed Meal Tolerance Tests (MMTT) were obtained for up to 24 months from 156 subjects with up to 3 months duration of type 1 diabetes at the time of study enrollment. These data provide the information needed to more accurately determine the sample size needed for future studies of the effects of new agents on the 2-hour area under the curve (AUC) of the C-peptide values. The natural log(x), log(x+1) and square-root (√x) transformations of the AUC were assessed. In general, a transformation of the data is needed to better satisfy the normality assumptions for commonly used statistical tests. Statistical analysis of the raw and transformed data are provided to estimate the mean levels over time and the residual variation in untreated subjects that allow sample size calculations for future studies at either 12 or 24 months of follow-up and among children 8-12 years of age, adolescents (13-17 years) and adults (18+ years). The sample size needed to detect a given relative (percentage) difference with treatment versus control is greater at 24 months than at 12 months of follow-up, and differs among age categories. Owing to greater residual variation among those 13-17 years of age, a larger sample size is required for this age group. Methods are also described for assessment of sample size for mixtures of subjects among the age categories. Statistical expressions are presented for the presentation of analyses of log(x+1) and √x transformed values in terms of the original units of measurement (pmol/ml). Analyses using different transformations are described for the TrialNet study of masked anti-CD20 (rituximab) versus masked placebo. These results provide the information needed to accurately evaluate the sample size for studies of new agents to preserve C-peptide levels in newly diagnosed type 1 diabetes.

SUBMITTER: Lachin JM

PROVIDER: S-EPMC3213096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceNear 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.ObjectiveTo 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 participantsThis 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.InterventionsRandom 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 measuresThe 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.ResultsAmong 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT04233034.

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Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes.

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