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.

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.

Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System.

CONTEXT: The apparent increased incidence of congenital hypothyroidism (CH) is partly due to increased detection of transient disease. OBJECTIVE: This work aims to identify predictors of transient CH (T-CH) and establish a predictive tool for its earlier differentiation from permanent CH (P-CH). METHODS: A retrospective cohort study was conducted of patients diagnosed with CH from 2006 to 2015 through Newborn Screening Ontario (NSO). RESULTS: Of 469 cases, 360 (76.8%) were diagnosed with P-CH vs 109 (23.2%) with T-CH. Doses of levothyroxine predicting T-CH were less than 3.9 µg/kg at age 6 months, less than 3.0 µg/kg at ages 1 and 2 years, and less than 2.5 µg/kg at age 3 years. Descriptive statistics and multivariable logistic modeling demonstrated several diverging key measures between patients with T-CH vs P-CH, with optimal stratification at age 1 year. Thyroid imaging was the strongest predictor (P < .001). Excluding imaging, significant predictors in the first year of life included thyroxine dose/kg (P < .001-.002), increase in thyrotropin (TSH) above the reference interval during treatment (P = .002), screening TSH (P = .03), and a history of maternal thyroid disease (P = .02). Based on the 1-year model without imaging, a risk score was developed to identify children with T-CH who may benefit from an earlier trial off therapy, to reduce excess medicalization and health care costs. CONCLUSION: A levothyroxine dose of less than 3 µg/kg at ages 1 and 2 years and less than 2.5 µg/kg at age 3 years can be predictive of T-CH. A novel risk score was developed that can be clinically applied to predict the likelihood of a successful trial off therapy for a given patient at age 1 year.

A rare unbalanced translocation (trisomy 5q33.3-qter, monosomy 13q34-qter) results in growth hormone deficiency and brain anomalies.

BACKGROUND: Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. METHODS: Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. RESULTS: Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. CONCLUSIONS: This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes.

Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample.

AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.

GAD-alum immunotherapy in type 1 diabetes expands bifunctional Th1/Th2 autoreactive CD4 T cells.

AIMS/HYPOTHESIS: Antigen-specific therapy aims to modify inflammatory T cell responses in type 1 diabetes and restore immune tolerance. One strategy employs GAD65 conjugated to aluminium hydroxide (GAD-alum) to take advantage of the T helper (Th)2-biasing adjuvant properties of alum and thereby regulate pathological Th1 autoimmunity. We explored the cellular and molecular mechanism of GAD-alum action in the setting of a previously reported randomised placebo-controlled clinical trial conducted by Type 1 Diabetes TrialNet. METHODS: In the clinical trial conducted by Type 1 Diabetes TrialNet, participants were immunised with 20 µg GAD-alum (twice or three times) or alum alone and peripheral blood mononuclear cell samples were banked at baseline and post treatment. In the present study, GAD-specific T cell responses were measured in these samples and GAD-specific T cell lines and clones were generated, which were then further characterised. RESULTS: At day 91 post immunisation, we detected GAD-specific IL-13+ CD4 T cell responses significantly more frequently in participants immunised with GAD-alum (71% and 94% treated twice or three times, respectively) compared with those immunised with alum alone (38%; p = 0.003 and p = 0.0002, respectively) accompanied by high secreted levels of IL-13, IL-4 and IL-5, confirming a GAD-specific, GAD-alum-induced Th2 response. Of note, GAD-specific, IL-13+ CD4 T cells observed after immunisation co-secreted IFN-γ, displaying a bifunctional Th1/Th2 phenotype. Single-cell transcriptome analysis identified IL13 and IFNG expression in concert with the canonical Th2 and Th1 transcription factor genes GATA3 and TBX21, respectively. T cell receptor ß-chain (TCRB) CDR3 regions of GAD-specific bifunctional T cells were identified in circulating naive and central memory CD4 T cell pools of non-immunised participants with new-onset type 1 diabetes and healthy individuals, suggesting the potential for bifunctional responses to be generated de novo by GAD-alum immunisation or via expansion from an existing public repertoire. CONCLUSIONS/INTERPRETATION: GAD-alum immunisation activates and propagates GAD-specific CD4 T cells with a distinctive bifunctional phenotype, the functional analysis of which might be important in understanding therapeutic responses.

Who Is Enrolling? The Path to Monitoring in Type 1 Diabetes TrialNet's Pathway to Prevention.

OBJECTIVE: To better understand potential facilitators of individual engagement in type 1 diabetes natural history and prevention studies through analysis of enrollment data in the TrialNet Pathway to Prevention (PTP) study. RESEARCH DESIGN AND METHODS: We used multivariable logistic regression models to examine continued engagement of eligible participants at two time points: 1) the return visit after screening to confirm an initial autoantibody-positive (Ab+) test result and 2) the initial oral glucose tolerance test (OGTT) for enrollment into the monitoring protocol. RESULTS: Of 5,387 subjects who screened positive for a single autoantibody (Ab), 4,204 (78%) returned for confirmatory Ab testing. Younger age was associated with increased odds of returning for Ab confirmation (age <12 years vs. >18 years: odds ratio [OR] 2.12, P < 0.0001). Racial and ethnic minorities were less likely to return for confirmation, particularly nonwhite non-Hispanic (OR 0.50, P < 0.0001) and Hispanic (OR 0.69, P = 0.0001) relative to non-Hispanic white subjects. Of 8,234 subjects, 5,442 (66%) were identified as eligible to be enrolled in PTP OGTT monitoring. Here, younger age and identification as multiple Ab+ were associated with increased odds of returning for OGTT monitoring (age <12 years vs. >18 years: OR 1.43, P < 0.0001; multiple Ab+: OR 1.36, P < 0.0001). Parents were less likely to enroll into monitoring than other relatives (OR 0.78, P = 0.004). Site-specific factors, including site volume and U.S. site versus international site, were also associated with differences in rates of return for Ab+ confirmation and enrollment into monitoring. CONCLUSIONS: These data confirm clear differences between successfully enrolled populations and those lost to follow-up, which can serve to identify strategies to increase ongoing participation.

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.).

Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes.

What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes? Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health-funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial-Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium's plans for the future.

GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis.

AIMS/HYPOTHESIS: GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. METHODS: In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). RESULTS: We estimate that there is a 98% probability that 20 µg GAD with alum administered twice yields a positive biological effect. The effect is probably a 15-20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between -0.250 and -0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of -0.294 pmol/ml at 1 year for untreated newly diagnosed patients. CONCLUSIONS/INTERPRETATION: The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

Prediction of congenital hypothyroidism based on initial screening thyroid-stimulating-hormone.

BACKGROUND: In thyroid-stimulating-hormone (TSH)-based newborn congenital hypothyroidism (CH) screening programs, the optimal screening-TSH cutoff level is critical to ensuring that true cases of CH are not missed. Screening-TSH results can also be used to predict the likelihood of CH and guide appropriate clinical management. The purpose of this study is to evaluate the predictive value of various screening-TSH levels in predicting a diagnosis of CH in the Ontario Newborn Screening Program (ONSP). METHODS: The initial screening and follow-up data of 444,744 full term infants born in Ontario, Canada from April 1, 2006 to March 31, 2010 were analyzed. Confirmed CH cases were based on local endocrinologists' report and initiation of thyroxine treatment. RESULTS: There were a total of 541 positive screening tests (~1/822 live births) of which 296 were true positives (~1:1,500 live births). Subjects were further subdivided based on screening-TSH and positive predictive values (PPV) were calculated. Twenty four percent in the 17-19.9 mIU/L range were true positives. In the 17-30 mIU/L range, 29 % were true positives with a significantly higher PPV for those sampled after (43 %) rather than before (25 %) 28 h of age (p < 0.02). Seventy three percent of neonates with an initial screening-TSH of ≥ 30 mIU/L and 97 % of those with ≥ 40 mIU/L were later confirmed to have CH. CONCLUSIONS: Infants with modestly elevated screening positive TSH levels between 17 and 19.9 mIU/L have a significant risk (24 %) of having CH. The very high frequency of true positives in term newborns with initial TSH values ≥ 30mIU/L suggests that this group should be referred directly to a pediatric endocrinologist in an effort to expedite further assessment and treatment. Screen positives with a modestly elevated TSH values (17-19.9 mIU/L) need to be examined in more detail with extended follow-up data to determine if they have transient or permanent CH.

Alternate approaches for pediatric type 1 diabetes drug development and potential regulatory approval: a perspective.

The incidence and prevalence of pediatric type 1 diabetes are increasing globally, including in the U.S. While the increasing number of cases of pediatric diabetes makes expeditious availability of new medical products and therapies for diabetes care essential, there have been many barriers encountered in bringing some drugs and devices to pediatric patients who may benefit. Newer insulins have been studied and approved for use in children. However, hurdles exist in the inclusion of children in studies of therapies aimed at preventing ß-cell loss in those with new-onset diabetes and those at risk for type 1 diabetes. This Perspective focuses on potential solutions to the challenges experienced in bringing new drugs for pediatric type 1 diabetes to marketing approval. Given their central importance as the users of medical products, patient perspectives are included along with scientific and regulatory considerations.

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

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.

Approach to the Infant with a Suspected Disorder of Sex Development.

A newborn with genital ambiguity requires careful diagnostic evaluation to identify the underlying etiology in an efficient manner and assign gender without lengthy delay. The infant's family needs comprehensive psychosocial support. Such infants should be referred to a multidisciplinary team with expertise in disorders of sex development.

Care of diabetes in children and adolescents: controversies, changes, and consensus.

Diabetes is one of the most common chronic medical disorders in children. The management of diabetes remains a substantial burden on children with diabetes and their families, despite improvements in treatment and rates of morbidity and mortality. Although most children with diabetes have type 1 diabetes, the increasing recognition of type 2 diabetes and genetic forms of diabetes in the paediatric population has important treatment implications. Diabetes therapy focuses strongly on targets for good metabolic control to reduce the risk of long-term complications. A parallel goal is to minimise short-term complications of hypoglycaemia and diabetic ketoacidosis. Technology offers opportunity for improvement in care, but has not yet fully lived up to its potential. New insights into the pathogenesis of diabetes and the development of new therapies have led to clinical trials aimed at the prevention of diabetes.