Objective
The aim of this study is to identify early markers of disease progression in order to facilitate more selectively targeted future clinical trials of disease modifying therapy.
Background Rationale
To date, there are no markers that predict response to therapy requiring year long studies to determine outcome. This results in slower progress and longer exposure of patients to drugs that may not be beneficial to them personally. By identifying early markers of response, treatment can be selected based on these markers and trials can be stopped at earlier time-points if clinical outcome is not beneficial.
Description of Project
A key challenge to developing new treatments for T1D is heterogeneity in the disease resulting in beneficial response in some people with treatment, but not others. Several factors may determine who responds beneficially to treatment. These include current immune status, change in immune status with treatment, and the natural rate of progression of disease. Thus, a better understanding of heterogeneity in immune and disease status may predict the trajectory of disease and these measures are essential to selective enrollment of those more likely to respond and/or allow for adaptive clinical trial designs in future clinical trials. The specific aim of this study is to identify early markers of disease progression in order to facilitate more selectively targeted future clinical trials of disease modifying therapy in a faster manner. Early immune and beta cell markers of response will be revealed through intensive monitoring prior to and during a short-course treatment of T1D subjects. We have selected abatacept treatment due to its proven benefit in some autoimmune subjects, including T1D subjects and the association of immune correlates with response. Immune parameters associated with response will be monitored before, during and after treatment to determine whether static (AIM 1) or short-term changes (AIM 2) in immune measures predict response to therapy at 1 year. Likewise, disease progression will be monitored before, during and after treatment, along with a 1 year outcome measure typical of current trials. While much has been learned from previous data and samples from clinical trials in T1D including the randomized clinical trial using abatacept, samples for this open label prospective study will be obtained at two time-points prior to treatment, much more frequently during treatment, and in sufficient quantity to assure multi-parameter assessments of both disease progression and immune features. In addition, disease progression will be monitored and analyzed in a more granular manner asking about rate of decline prior to treatment as compared to hypothesized leveling of the rate of decline with treatment as may be seen in responders. Both pre-treatment and during treatment rates of disease progression will be compared to post-treatment changes to determine persistence of treatment effects. Overall, this study will identify early markers of treatment response potentially leading to smaller and faster trials and more personalized selection of treatments.
Anticipated Outcome
Based on past experience, we predict that some individuals will respond to treatment while others will not. We expect to be able to define immune features prior to treatment or changes early upon treatment that will predict response.
Relevance to T1D
This study will directly address what patients will best benefit from abatacept treatment. Beyond this goal, we will also learn more about patient heterogeneity and rate of disease progression in recent onset subjects that will help in the more elegant design of future studies.