Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. In relatives of patients with type 1 diabetes (T1DM) at risk for disease development, randomization to teplizumab delayed time to T1DM diagnosis compared to placebo treated patients.

2. Adverse events associated with teplizumab treatment included rash and transient lymphopenia.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

T1DM results from autoimmune destruction of insulin-producing beta cells. Before frank insulin production deficits or dysglycemia arise autoantibodies are produced in patients at risk for T1DM. The Fc receptor-nonbinding anti-CD3 antibody teplizumab has been shown to reduce loss of beta cells after the diagnosis of T1DM, and whether is can slow progression to diagnosis in at-risk patients is unknown. This phase 2 randomized controlled trial showed a significant delay until T1DM diagnosis in high risk patients compared to placebo treated patients. Adverse events of rash and transient lymphopenia were observed in the treatment group. T-cells associated with unresponsiveness and downregulation of autoimmune activity were more common in teplizumab treated patients than those in the placebo group.

This randomized controlled trial suggests possible first-in-class efficacy of teplizumab for prophylactic delay of T1DM onset in high risk patients. The study is limited by the small trial size and its generalizability towards people at risk for T1DM without diagnosed first degree relatives is unknown.

In-Depth [randomized controlled trial]:

This phase 2, international, placebo and randomized controlled trial enrolled patients between 2011 and 2018. Eligible patients were 8 years of age or older with relatives who had T1DM, were not yet diagnosed with T1DM, and had 2 or more autoantibodies present related to diabetes. Patients had to have dysglycemia during an oral glucose tolerance test. Patients were randomized to either teplizumab (n=44)or placebo (n=32) groups. Patients received intravenous treatment or placebo according to a scheduled regimen from day 0-13 of the study. Patients were followed for out to approx. 60 months. The primary outcome of median elapsed time until clinical T1DM diagnosis was 48.4 months in the treatment group and 24.4 months in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.22 to 0.78; two-sided P=0.006). Annualized rates of T1DM diagnosis were 14.9% and 35.9% per year in the treatment and placebo groups, respectfully. The first year after trial entry showed the largest treatment affect, with 7% vs 44% of treatment and placebo patients diagnosed, respectfully (unadjusted hazard ratio, 0.13; 95% CI, 0.05 to 0.34). In teplizumab patients lymphocyte counts decreased to a low by day 5 (total decrease, 72.3%; interquartile range, 82.1 to 68.4; P<0.001). Of the grade 3 adverse events, 15/20 in the treatment group involved lymphopenia. KLRG1+TIGIT+EOMES+CD8+ T-cells which are associated with T-cell unresponsiveness were more common in treated patients. In subgroup analysis, almost all subgroup hazard ratios suggested better T1DM diagnosis outcomes in teplizumab treated patients.

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