Strategies for clinical trials in type 1 diabetes

Abstract

During the past one to two decades, substantial progress has been made in our understanding of the immunopathology of type 1 diabetes (T1D) and the potential for immune interventions that can alter the natural history of the disease. This progress has resulted from the use of standardized study designs, endpoints, and, to a certain extent, mechanistic analyses in intervention trials in the setting of new-onset T1D. To date, most of these trials have involved single-agent interventions but, increasingly, future trials will test therapeutic combinations that are based on a compelling scientific rationale and testable mechanistic hypotheses. These increasingly complex trials will benefit from novel trial designs (such as factorial or adaptive designs), enhanced clinical endpoints that more directly assess islet pathology (such as β-cell death assays and islet or pancreatic imaging), improved responder analyses, and sophisticated mechanistic assays that provide deep phenotyping of lymphocyte subsets, gene expression profiling, in vitro T cell functional assessments, and antigen-specific responses. With this developing armamentarium of enhanced trial designs, endpoints, and clinical and mechanistic response analyses, we can expect substantial progress in better understanding the breakdown in immunologic tolerance in T1D and how to restore it to achieve significant and long-lasting preservation of islet function.

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

“…A response-adaptive design has been employed to develop an immunomodulatory treatment protocol that increases immune regulation within physiological levels to restore health while preserving pathogen responses in participants with T1D. This experimental medicine approach of defining a treatment regimen based on our understanding of the immunopathogenesis of the disease prior to testing clinical efficacy contrasts with current strategies of conducting traditional randomized, double-blind placebo control trials that test efficacy first with limited success (20,21).…”

Enforcing the checkpoints: harnessing T-cell exhaustion for therapy of T1D

“…Type 1 diabetes (T1D) is a prototypic autoimmune disease in which insulin secreting islet beta cells are destroyed by immune cells when tolerance mechanisms fail. Thus, it is important to identify therapies that deplete or inactivate harmful autoreactive cells in addition to enhancing immune tolerance that will prevent the resurgence of autoimmunity [1]. However, to date, no single treatment modality has been shown to persistently prevent progression of T1D in the majority of treated patients [2], most likely because of the failure to maintain enhanced peripheral tolerance.…”

Carbamazepine, a beta-cell protecting drug, reduces type 1 diabetes incidence in NOD mice

“…The vast majority of type 1 diabetes clinical trials have focused on selective immune suppression and no approved therapies have been developed that directly protect beta-cells by promoting cellular health and function 1 . There is a lack of information on the molecular mechanisms of beta-cell death in type 1 diabetes, and only few examples of viable drug targets exploitable for beta-cell protection in vivo 2 .…”