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

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.