T cell directed therapy, anti-thymocyte globulin (ATG), in low doses, has been shown to lower HbA1c and preserve endogenous insulin production (measured by C-peptide) in individuals with recently diagnosed type 1 diabetes (T1D). However, not all individuals who received ATG responded to the therapy (i.e., non-responders). Additionally, use of ATG alone does not address inherent beta cell stress. A calcium channel blocker, verapamil, has demonstrated C-peptide preservation in newly diagnosed T1D. Investigators will identify those mostly likely to respond to ATG using an ex vivo predictive biomarker of response to ATG. In addition, Investigators will use sequential therapies to increase efficacy (ATG followed by verapamil) and explore synergistic mechanisms. This will be assessing with in depth immunophenotyping and quantify biomarkers of beta cell stress, cell death, and abnormal prohormone processing. Finally, novel clinical trial endpoints will be assessed for their ability to predict treatment efficacy earlier than the standard endpoint at 1 year.
Investigators will conduct a phase 2 1:1 randomized controlled and blinded trial in Aim 1 comparing stimulated C-peptide (and other measures) between those treated with low-dose ATG and those treated with placebo. Co-primary endpoints include the difference between mean ATG and placebo values of the 2-hr mixed meal tolerance test (MMTT)-stimulated area under the curve (AUC) C-peptide at 12 months (standard T1D trial measure) and the difference between the change in the same measure over the first 6 months. Participants will be stratified based on their ex vivo immune responder signature to allow an equal number of "responders" and "non-responders" in both treatment arms. Following each participant's completion of this 1 year randomized controlled trial (RCT) they will enter Aim 2 and be re-randomized to received verapamil or not in an open-label 1 year extension where mechanistic endpoints will be explored related to immunophenotyping, gene expression, DNA methylation and beta cell markers including markers of beta cell stress and death as well as markers of abnormal prohormone processing.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
ATG (brand name Thymoglobulin) a polyclonal T cell antibody preparation. It will be given at low doses (0.5 mg/kg Day 1 then 2 mg/kg Day 2).
Open label administration at 120, 240 or 360 mg daily based on weight and ECG findings
I.V. Saline
Barbara Davis Center for Diabetes
Aurora, Colorado, United States
RECRUITINGUniversity of Florida
Gainesville, Florida, United States
RECRUITINGAUC C-peptide between ATG and placebo values
mean difference between ATG and placebo values of the 2-hr mixed meal tolerance test (MMTT)-stimulated area under the curve (AUC) C-peptide at 12 months
Time frame: 12 Months
Change in 2-hr MMTT AUC C-peptide
mean difference between the change in 2-hr MMTT stimulated AUC C-peptide
Time frame: 6 months
Immune and beta cell mechanistic analyses
To explore mechanisms of synergy between ATG received in year 1 and the addition of open-label verapamil in year 2.
Time frame: 6, 12, 18, 24 months
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