Defining pathways for development of disease-modifying therapies in children with type 1 diabetes: a consensus report

Abstract

Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies.

Figure 1

Mean HbA_1c levels by age. Circles represent mean HbA_1c values for each year of age from 16,057 T1D Exchange registry participants. Participants aged <4 years were grouped as age 4 and those aged ≥75 years were grouped as age 75. Shaded area represents the 95% CI around smoothed line. Numbers next to circles are the N for each year of age. Reprinted with permission from Miller et al. (10).

Figure 2

Impact of age on risk for disease progression in antibody-positive relatives participating in TrialNet Pathway to Prevention Study. A: Life table of progression to diabetes according to age in double antibody–positive relatives. B: Life table of progression to diabetes according to age in double antibody–positive subjects from time of abnormal glucose tolerance.

Figure 3

Impact of age on C-peptide after diagnosis. A: Model-based estimates of average slopes of C-peptide area under the curve (AUC) over time according to age quartiles (age-groups 7.7–12.3 years, 12.4–14.7 years, 14.8–21.2 years, and 21.4–46.1 years). Data from 191 TrialNet clinical trial participants. Reprinted with permission from Greenbaum et al. (63). B: Proportion of participants with detectable (≥0.017 nmol/L) nonfasting C-peptide according to age at diagnosis and duration of type 1 diabetes. White bars, those diagnosed at age ≤18 years; black bars, those diagnosed at age >18 years. Data from the T1D Exchange residual insulin study. Reprinted with permission from Davis et al. (64).

Figure 4

Impact of age on response to disease-modifying therapy. A: C-peptide over time in TrialNet participants randomized to treatment with rituximab (blue line) or placebo (red line) who were aged <18 years (solid lines) or aged ≥18 years (dashed lines) at the time of randomization (69). B: C-peptide over time in TrialNet participants randomized to treatment with abatacept (blue line) or placebo (red line) who were aged <18 years (solid lines) or aged ≥18 years (dashed lines) at the time of randomization (66).