Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients.

Here we report a unique situation in which an early and synchronized Epstein-Barr virus (EBV) reactivation was induced by a 6-day course of treatment with a humanized CD3-specific monoclonal antibody in patients with recent onset of type 1 diabetes. The virologic and immunologic analysis demonstrated that this reactivation was transient, self-limited, and isolated, associated with the rapid advent of an EBV-specific T-cell response. The anti-CD3 antibody administration induced short-lasting immunosuppression and minor yet clear-cut signs of T-cell activation that preceded viral reactivation. Early posttransplant monitoring of renal and islet allograft recipients showed that no comparable phenomenon was observed after the administration of full-dose immunosuppressive therapy. This EBV reactivation remains of no apparent clinical concern over the long term and should not preclude further development of therapeutic anti-CD3 antibodies. This phenomenon may also direct new research avenues to understand the still ill-defined nature of stimuli triggering EBV reactivation in vivo.

Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.

BACKGROUND: Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease that leads to a major loss of insulin-secreting beta cells. The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3). METHODS: In a multicenter study, 80 patients with new-onset type 1 diabetes were randomly assigned to receive placebo or ChAglyCD3 for six consecutive days. Patients were followed for 18 months, during which their daily insulin needs and residual beta-cell function were assessed according to glucose-clamp-induced C-peptide release before and after the administration of glucagon. RESULTS: At 6, 12, and 18 months, residual beta-cell function was better maintained with ChAglyCD3 than with placebo. The insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced among patients with initial residual beta-cell function at or above the 50th percentile of the 80 patients. In this subgroup, the mean insulin dose at 18 months was 0.22 IU per kilogram of body weight per day with ChAglyCD3, as compared with 0.61 IU per kilogram with placebo (P<0.001). In this subgroup, 12 of 16 patients who received ChAglyCD3 (75 percent) received minimal doses of insulin (< or =0.25 IU per kilogram per day) as compared with none of the 21 patients who received placebo. Administration of ChAglyCD3 was associated with a moderate "flu-like" syndrome and transient symptoms of Epstein-Barr viral mononucleosis. CONCLUSIONS: Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study.

OBJECTIVE: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. METHODS: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). RESULTS: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. CONCLUSIONS: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and ß-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602.

Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents.

BACKGROUND: The development of type 1 diabetes mellitus is preceded by autoimmunity against islet beta cells. OBJECTIVE: To determine the risk for islet autoimmunity and childhood diabetes in offspring of affected parents. DESIGN: Prospective cohort study. SETTING: German BABYDIAB study. PARTICIPANTS: 1610 offspring of parents with type 1 diabetes. MEASUREMENTS: Autoantibodies to islet autoantigens were measured at 9 months, 2 years, 5 years, and 8 years of age. RESULTS: By 5 years of age, the frequency of islet autoantibodies was 5.9% (95% CI, 4.6% to 7.2%), the frequency of multiple islet autoantibodies was 3.5% (CI, 2.5% to 4.5%), and the frequency of diabetes was 1.5% (CI, 0.9% to 2.1%). The risk for diabetes was highest in offspring with multiple autoantibodies (40% within 5 years vs. 3% in offspring with single autoantibodies; P = 0.005). Progression to multiple islet autoantibodies was fastest in children who were autoantibody positive by age 2 years (P < 0.001), and progression to diabetes was inversely related to the age of positivity for multiple autoantibodies (P = 0.02). LIMITATIONS: The findings are limited to childhood diabetes in affected families. CONCLUSIONS: Childhood autoimmune diabetes is associated with autoimmunity that starts before 2 years of age.

IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes.

OBJECTIVE: Children of affected probands are at increased risk for type 1 diabetes. The objective of this study was to determine and stratify the risk for islet autoimmunity and childhood diabetes in newborn offspring of affected parents using family history and HLA genetic markers. RESEARCH DESIGN AND METHODS: Antibodies to islet autoantigens were measured at ages 9 months, 2 years, 5 years, and 8 years in 1,610 offspring of parents with type 1 diabetes participating in the German BABYDIAB study. HLA DR and DQ genetic typing was performed. Family history of type 1 diabetes was obtained from questionnaires. RESULTS: Extensive family history of type 1 diabetes and HLA DR/DQ genotyping were associated with islet autoantibody and diabetes risks. Significant contributions to the child's risk for developing islet autoantibodies and type 1 diabetes were conferred by a multiple first-degree family history of type 1 diabetes (two parents or one parent and a sibling; adjusted hazard [HR] ratio, 6.2 for multiple islet autoantibodies and 7.8 for type 1 diabetes), high-risk HLA genotypes (adjusted HR, 11 and 10.9), and moderate-risk HLA genotypes (adjusted HR, 6.3 and 4.3) in a multivariate analysis. Combining these factors stratified the risk for islet autoantibodies from 1 to 46% and for type 1 diabetes from 0 to 19.5% by 5 years of age. CONCLUSIONS: Risk of childhood diabetes in affected families can be stratified using a combination of genetic and family history markers very early in life.

No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes.

OBJECTIVE: To determine whether daily intake of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is safe and improves beta-cell function in patients with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS: Safety was assessed in an open study of 25 patients aged 18-39 years with recent-onset type 1 diabetes who received 0.25 microg 1,25(OH)(2)D(3) daily for 9 months. An additional 40 patients were randomly assigned to 0.25 microg 1,25(OH)(2)D(3) or placebo daily for 9 months and followed for a total of 18 months for safety, beta-cell function, insulin requirement, and glycemic control. RESULTS: Safety assessment showed values in the normal range in nearly all patients, regardless of whether they received 1,25(OH)(2)D(3) or placebo. No differences in AUC C-peptide, peak C-peptide, and fasting C-peptide after a mixed-meal tolerance test between the treatment and placebo groups were observed at 9 and 18 months after study entry, with approximately 40% loss for each parameter over the 18-month period. A1C and daily insulin requirement were similar between treatment and placebo groups throughout the study follow-up period. CONCLUSIONS: Treatment with 1,25(OH)(2)D(3) at a daily dose of 0.25 microg was safe but did not reduce loss of beta-cell function.

No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes.

OBJECTIVE: This randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves beta-cell function in patients with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 188 patients, aged 10-35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied. RESULTS: The mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by approximately 60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed. CONCLUSIONS: Treatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain beta-cell function.