Type 1 diabetes research and clinical trials will continue to fail to meet their goals until several knowledge gaps are acknowledged and addressed, according to a paper recently published in The Journal of Clinical Endocrinology & Metabolism.
The perspective article, by David Bleich, MD, of Rutgers New Jersey Medical School in Rutgers, N.J., and David H. Wagner, of the University of Colorado Anschutz Medical Center in Aurora, Colo., points out that four major clinical insulin trials have been conducted to prevent type 1 diabetes, and each has failed to meet its outcome to date. “The recent failed TrialNet study, titled Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients with Type 1 Diabetes, was both disappointing and predictable,” the authors write. “Numerous studies using insulin in differing configurations have consistently demonstrated lack of efficacy in preventing human type 1 diabetes.”
Bleich and Wagner reviewed high-quality peer-reviewed basic science and clinical trials on type 1 diabetes from 2000 to 2018 using Google Scholar and PubMed reference databases. They noticed that one reason for these continued failures is a uniform protocol for antigen-specific immunotherapy. “One reason for persistent failure of type 1 diabetes studies is an overgeneralized clinical approach that involves disease stratification; not every patient at risk for type 1 diabetes has pathogenic immune effector T cells that are responsive to insulin or another single specific autoantigen,” they write.
Here, true personalized or precision medicine should come into play, recognizing that each individual has “phenotypic and genotypic quirks that distinguish them from other study participants.” “An alternative approach using molecular tools to personalize the preventive treatment strategy might be a road forward for type 1 diabetes research,” Bleich and Wagner write.
The authors then lay out their idea for designing a clinical type 1 diabetes prevention trial. They write that a randomized, double-blind, placebo-controlled trial will not work because there are too many variables in each person to control: (1) autoantigen number, (2) antigen dosing, and (3) T-cell receptor (TCR) rearrangement. “Perhaps a prospective cohort study design would be useful,” they write, “whereby each study participant received a personalized immune tolerance protocol, thus a precision medicine approach for the 21st century.”
The authors conclude that T-cell and genetic studies are necessary before starting a robust prospective cohort type 1 diabetes trial in order to ensure success. “We will never know why the recent TrialNet oral insulin study failed without appropriate T-cell studies,” Bleich and Wagner write. “These study results are forthcoming and might provide important clues to why it did not work.”