Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

OBJECTIVE: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve ß-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. RESEARCH DESIGN AND METHODS: We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. RESULTS: Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants. CONCLUSIONS: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.

Longitudinal Assessment of Pancreas Volume by MRI Predicts Progression to Stage 3 Type 1 Diabetes.

OBJECTIVE: This multicenter prospective cohort study compared pancreas volume as assessed by MRI, metabolic scores derived from oral glucose tolerance testing (OGTT), and a combination of pancreas volume and metabolic scores for predicting progression to stage 3 type 1 diabetes (T1D) in individuals with multiple diabetes-related autoantibodies. RESEARCH DESIGN AND METHODS: Pancreas MRI was performed in 65 multiple autoantibody-positive participants enrolled in the Type 1 Diabetes TrialNet Pathway to Prevention study. Prediction of progression to stage 3 T1D was assessed using pancreas volume index (PVI), OGTT-derived Index60 score and Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), and a combination of PVI and DPTRS. RESULTS: PVI, Index60, and DPTRS were all significantly different at study entry in 11 individuals who subsequently experienced progression to stage 3 T1D compared with 54 participants who did not experience progression (P < 0.005). PVI did not correlate with metabolic testing across individual study participants. PVI declined longitudinally in the 11 individuals diagnosed with stage 3 T1D, whereas Index60 and DPTRS increased. The area under the receiver operating characteristic curve for predicting progression to stage 3 from measurements at study entry was 0.76 for PVI, 0.79 for Index60, 0.79 for DPTRS, and 0.91 for PVI plus DPTRS. CONCLUSIONS: These findings suggest that measures of pancreas volume and metabolism reflect distinct components of risk for developing stage 3 type 1 diabetes and that a combination of these measures may provide superior prediction than either alone.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials.

Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown. Objective: To identify factors associated with screening for T1D prevention trials. Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual. Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates. Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.

IL-6 receptor blockade does not slow ß cell loss in new-onset type 1 diabetes.

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual ß cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual ß cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Repeatability and Reproducibility of Pancreas Volume Measurements Using MRI.

Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs that correspond to excellent clinical significance (ICC > 0.9), are not related to changes in stomach volume, and could be a useful tool for clinical investigation of diabetes and other pancreas pathologies.

Correlating maternal iodine status with neonatal thyroid function in two hospital populations in Ghana: a multicenter cross-sectional pilot study.

BACKGROUND: Congenital hypothyroidism is a common, yet easily treatable cause of poor growth and intellectual disability. Newborn screening programs play an important role in the early detection and treatment of congenital hypothyroidism. However, an estimated 71% of children are born in countries such as Ghana, which does not have a screening program. Iodine deficiency, a common cause of congenital hypothyroidism, is present in the Ghanaian population. Mild to moderate maternal iodine deficiency may negatively impact cognitive function in children. A structured approach to examine the association between maternal iodine levels and infant thyroid function may have important ramifications on our understanding of congenital hypothyroidism in Ghana. We investigated the hypothesis that maternal iodine deficiency impacts infant thyroid function, using Thyroid Stimulating Hormone (TSH) as a marker of thyroid function. We also explored potential opportunities and barriers to newborn screening for congenital hypothyroidism in Ghana. METHODS: This was a cross-sectional, multicenter pilot study of 250 women and their neonates recruited from post-natal clinics in Accra and Tamale, Ghana. We compared maternal urine iodine concentration and infant TSH, as well as maternal sociodemographic and nutrition information. Regression models were used to model the relationship between variables. RESULTS: Median infant TSH was 4.7 µIU/ml (95% CI: 3.9-5.5) in Accra. In Tamale, the median infant TSH was 3.5 µIU/ml (95%CI: 3.3 to 3.6) (Δ: 1.3 µIU/ml, 95% CI: 0.5-2.1, p = 0.002). Median maternal urine iodine concentrations were 141.0 µg/L (95% CI: 115.7 to 166.3) and 142.5 µg/L (95% CI: 125.1 to 160.0) in Accra and Tamale, respectively (Δ: - 1.5 µIU/ml, 95% CI: - 32.2 - 29.2, p = 0.925). There was a weakly positive correlation between maternal urine iodine and infant TSH (rho 0.1, p = 0.02). Almost one-third (30%) of women in both locations had biochemical evidence of iodine deficiency. Mothers with any formal education were more likely to have higher iodine levels than their counterparts who had no formal education (coefficient 0.31, p = 0.006). CONCLUSIONS: Maternal iodine deficiency is prevalent in Ghana and is correlated to infant thyroid function. We recommend studies with larger sample sizes to assess the true scope of this relationship.

The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening.

AIMS/HYPOTHESIS: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. METHODS: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. RESULTS: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%. CONCLUSIONS/INTERPRETATION: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).