American Diabetes Association
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Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials

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posted on 2024-04-15, 22:52 authored by Laura M. Jacobsen, David Cuthbertson, Brian N. Bundy, Mark A. Atkinson, Wayne Moore, Michael J. Haller, William E. Russell, Stephen E. Gitelman, Kevan C. Herold, Maria J. Redondo, Emily K. Sims, Diane K. Wherrett, Antoinette Moran, Alberto Pugliese, Peter A. Gottlieb, Jay M. Sosenko, Heba M. Ismail

Objective: Mixed meal tolerance test stimulated area under the curve (AUC) C-peptide at 12 to 24 months represents the primary endpoint for nearly all intervention trials seeking to preserve beta cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months post-therapy. Such findings would support shorter trials to establish initial efficacy.

Research Design and Methods: We examined data from 6 TrialNet immunotherapy randomized controlled trials in a post-hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial.

Results: Among trials meeting their primary endpoint, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (p=0.030 and <0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value=0.80, p<0.001), and supported the concept of smaller trial sizes down to 54 participants.

Conclusions: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early phase clinical trials.


The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061040, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, Contract No. HHSN267200800019C, and the JDRF. This work is supported in part by the NIH/NCATS Clinical and Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, UL1 TR001085, UL1 TR001427, UL1 TR001863, UL1 TR001082, UL1 TR000114, UL1 TR001857, UL1 TR000445, UL1 TR002529, UL1 TR001872, UL1 TR002243, and PO1 NIH AI-42288, and a general clinical research center award (M01 RR00400). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF. Vanderbilt UL1TR002243. LMJ (K08DK128628-01) and HMI (K23DK129799) are funded by the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health NIH. HMI is also funded by the Doris Duke Charitable Foundation through the COVID‐19 Fund to Retain Clinical Scientists Collaborative Grant Program (Grant 2021258) and The John Templeton Foundation (Grant 62288), and the Pilot and Feasibility Grant from the Indiana Center for Diabetes and Metabolic Diseases (P30DK097512).


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