Introduction and Objective: C-peptide is the most reliable biomarker of β-cell function in type 1 diabetes (T1D) and is strongly associated with glycemic control and risk of complications. We propose estimate of time to minimum residual C-peptide (TMRCP), which uses all available longitudinal data, to serve as an efficacy measure in T1D trials. Methods: TMRCP is defined as the time until C-peptide levels decline to a prespecified value representing functional loss of β-cell secretory capacity. We estimate it using a nonlinear mixed-effects model applied to log-transformed mean area under curve (MAUC) C-peptide values from mixed-meal tolerance testing. This approach makes efficient use of all available longitudinal measurements, appropriately accounts for repeated observations within individuals and variable visit schedules or incomplete follow-up, and provides subject-specific TMRCP estimates. Results: We applied the TMRCP estimation framework to six randomized, placebo-controlled, double-blind trials conducted by TrialNet in recent-onset T1D patients (total N=597). Using Wilcoxon rank-sum test on TMRCP estimates, we identified the same three treatments as effective as the original analyses. Compared to the corresponding placebo group, median TMRCP for the three effective treatments were 128 vs 84 days for Rituximab (p=0.034), 92 vs 70 days for Abatacept (p=0.030), and 110 vs 53 days for anti-thymocyte globulin (p=0.027), while the differences were less than 4 days for the three non-effective treatments (mycophenolate mofetil and daclizumab combined therapy, glutamic acid decarboxylase, and canakinumab). Conclusion: Unlike fixed-time endpoints, TMRCP leverages full longitudinal data to measure loss of residual insulin secretion and provides subject-specific estimates that support robust treatment comparisons. We conclude that TMRCP is a clinically interpretable and statistically efficient endpoint for future T1D intervention studies. Disclosure A.A. Ding: None. J. Krischer: None. H. Gao: None. H. Rodriguez: Advisory Panel; Ended; MannKind Corporation. Research Support; Current; Sanofi. Speaker's Bureau; Ended; Sanofi. Research Support; Ended; MannKind Corporation. Research Support; Current; Lilly. Other - DSMB; Ended; Merck Sharp Current; Sanofi. Research Support; Ended; Novo Nordisk. Research Support; Current; Zucara Therapeutics. Research Support; Ended; Dexcom, Inc. Research Support; Current; Cour Pharma. Research Support; Ended; MannKind Corporation. S.S. Wu: Consultant; Current; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Current; United HealthCare Services, Inc. Funding National Institutes of Health (5U01 DK106993)
Ding et al. (Fri,) studied this question.