Background The immunopathogenesis of type 1 diabetes mellitus (T1DM) is associated with T-lymphocyte autoimmunity. To be fully active, immune T-lymphocytes require a co-stimulatory signal in addition to the main antigen driven signal. Abatacept modulates co-stimulation andprevents full T-lymphocyte activation. We evaluated the effect of abatacept in recent-onset T1DM. Methods In this multicentre, double-masked, randomised controlled trial, 112 subjects (ages 6–36) recently diagnosed with T1DM; 77 received abatacept (10 mg/kg, maximum 1000 mg/dose) and 35 received placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over two years. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at two years. Secondary outcomes include difference between groups in incidence of loss of peak C-peptide to < 0·2 pmol/ml, slope of C-peptide over time, changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00505375). Findings Adjusted C-peptide AUC was 59% (95% CI: 6·1%, 112%) higher at two years with abatacept (0·378 pmol/ml) versus placebo (0·238 pmol/ml) (p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months’ delay in decline with abatacept. There was lower HbA1c (p<0·002) but similar insulin use. There were few, clinically not significant infusion related adverse events and minimal overall adverse events. There was no increase in infections or neutropenia. Interpretation Co-stimulation modulation with abatacept slowed decline of beta cell function over two years. The beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM. Yet, despite continued administration of abatacept over 24 months, the decline in beta cell function with abatacept was parallel to that with placebo after six months of treatment, causing us to speculate that T-lymphocyte activation may lessen with time. Further observation will determine whether the beneficial effect continues after cessation of abatacept infusions. Funding National Institutes of Health.
Background Type 1 diabetes (T1DM) is an autoimmune disease leading to destruction of insulin producing beta cells and life-long requirement for insulin therapy. Glutamic acid decarboxylase (GAD) is a major target of this immune response. Studies in animal models of autoimmunity have shown that treatment with a target antigen can modulate aggressive autoimmunity. We evaluated immunization with GAD formulated in aluminum hydroxide (alum) as an adjuvant in recent onset T1DM. Methods In this multicentre, double-masked, randomised controlled trial, 145 subjects (ages 3-45) with T1DM for less than 3 months received 3 injections of 20 μg GAD-alum (48 subjects), 2 injections of GAD-alum and one of alum alone (49 subjects) or 3 injections of alum (48 subjects) subcutaneously at baseline, 4 weeks later and 8 weeks after the second injection. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at one year. Secondary outcomes included changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00529399). Findings The ratio (experimental to control) of the adjusted population mean of C-peptide for the GAD-alum ×3 and GAD-alum ×2/alum ×1 groups is 0.998 (95% CI: [0.779, 1.22], p = 0.98) and 0.926 (95% CI: [0.720, 1.13], p = 0.50), respectively. HbA1c and insulin use did not differ between groups. There was no difference in rate or severity of adverse events between groups. Interpretation Antigen-based immunotherapy therapy using GAD-alum given subcutaneously in two or three doses over 4 to 12 weeks does not alter the course of loss of insulin secretion over one year in subjects with recently diagnosed T1DM. While antigen-based therapy is a highly desireable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. Funding National Institutes of Health.
BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent betweengroup difference in glycemic control or adverse events. Alefacept treatment depleted CD4 + and CD8 + central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1 + CD4+ Tem and Tcm (P < 0.01).CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.FUNDING. NIH and Astellas.
; for the CGM Intervention in Teens and Young Adults with T1D (CITY) Study Group IMPORTANCE Adolescents and young adults with type 1 diabetes exhibit the worst glycemic control among individuals with type 1 diabetes across the lifespan. Although continuous glucose monitoring (CGM) has been shown to improve glycemic control in adults, its benefit in adolescents and young adults has not been demonstrated. OBJECTIVE To determine the effect of CGM on glycemic control in adolescents and young adults with type 1 diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted between January 2018 and May 2019 at 14 endocrinology practices in the US including 153 individuals aged 14 to 24 years with type 1 diabetes and screening hemoglobin A 1c (HbA 1c) of 7.5% to 10.9%. INTERVENTIONS Participants were randomized 1:1 to undergo CGM (CGM group; n = 74) or usual care using a blood glucose meter for glucose monitoring (blood glucose monitoring [BGM] group; n = 79). MAIN OUTCOMES AND MEASURES The primary outcome was change in HbA 1c from baseline to 26 weeks. There were 20 secondary outcomes, including additional HbA 1c outcomes, CGM glucose metrics, and patient-reported outcomes with adjustment for multiple comparisons to control for the false discovery rate. RESULTS Among the 153 participants (mean [SD] age, 17 [3] years; 76 [50%] were female; mean [SD] diabetes duration, 9 [5] years), 142 (93%) completed the study. In the CGM group, 68% of participants used CGM at least 5 days per week in month 6. Mean HbA 1c was 8.9% at baseline and 8.5% at 26 weeks in the CGM group and 8.9% at both baseline and 26 weeks in the BGM group (adjusted between-group difference, −0.37% [95% CI, −0.66% to −0.08%]; P = .01). Of 20 prespecified secondary outcomes, there were statistically significant differences in 3 of 7 binary HbA 1c outcomes, 8 of 9 CGM metrics, and 1 of 4 patient-reported outcomes. The most commonly reported adverse events in the CGM and BGM groups were severe hypoglycemia (3 participants with an event in the CGM group and 2 in the BGM group), hyperglycemia/ketosis (1 participant with an event in CGM group and 4 in the BGM group), and diabetic ketoacidosis (3 participants with an event in the CGM group and 1 in the BGM group). CONCLUSIONS AND RELEVANCE Among adolescents and young adults with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in glycemic control over 26 weeks. Further research is needed to understand the clinical importance of the findings.
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