Enhancing pediatric clinical trial feasibility through the use of Bayesian statistics.

BackgroundPediatric clinical trials commonly experience recruitment challenges including limited number of patients and investigators, inclusion/exclusion criteria that further reduce the patient pool, and a competitive research landscape created by pediatric regulatory commitments. To overcome these challenges, innovative approaches are needed.MethodsThis article explores the use of Bayesian statistics to improve pediatric trial feasibility, using pediatric Type-2 diabetes as an example. Data for six therapies approved for adults were used to perform simulations to determine the impact on pediatric trial size.ResultsWhen the number of adult patients contributing to the simulation was assumed to be the same as the number of patients to be enrolled in the pediatric trial, the pediatric trial size was reduced by 75-78% when compared with a frequentist statistical approach, but was associated with a 34-45% false-positive rate. In subsequent simulations, greater control was exerted over the false-positive rate by decreasing the contribution of the adult data. A 30-33% reduction in trial size was achieved when false-positives were held to less than 10%.ConclusionReducing the trial size through the use of Bayesian statistics would facilitate completion of pediatric trials, enabling drugs to be labeled appropriately for children.

Addressing Unmet Medical Needs in Type 1 Diabetes: A Review of Drugs Under Development.

INTRODUCTION: The incidence of type 1 diabetes (T1D) is increasing worldwide and there is a very large need for effective therapies. Essentially no therapies other than insulin are currently approved for the treatment of T1D. Drugs already in use for type 2 diabetes and many new drugs are under clinical development for T1D, including compounds with both established and new mechanisms of action. Content of the Review: Most of the new compounds in clinical development are currently in Phase 1 and 2. Drug classes discussed in this review include new insulins, SGLT inhibitors, GLP-1 agonists, immunomodulatory drugs including autoantigens and anti-cytokines, agents that regenerate ß-cells and others. Regulatory Considerations: In addition, considerations are provided with regard to the regulatory environment for the clinical development of drugs for T1D, with a focus on the United States Food and Drug Administration and the European Medicines Agency. Future opportunities, such as combination treatments of immunomodulatory and beta-cell regenerating therapies, are also discussed.

Addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development.

The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti-inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors.

Unmasking of Partial Diabetes Insipidus during Stress but Not Maintenance Dosing of Glucocorticoids in an Infant with Septo-Optic Dysplasia.

Background. It is well acknowledged that glucocorticoid (GC) replacement can unmask diabetes insipidus (DI) in subjects with hypopituitarism. Objective. To increase the awareness and monitoring for transient and symptomatic DI in children with partial hypopituitarism during periods in which increased GC needs are required. Methods/Case. A 2-month-old female infant with septo-optic dysplasia (SOD; on thyroid and maintenance GC replacement therapy at 8 mg/m(2)/day) developed transient DI during 2 separate episodes of stress (one hypothermia, one febrile) when stress dosing of GC (25 mg/m(2)/day) was instituted. Conclusion. Children not diagnosed with DI during initial evaluation for hypopituitarism may benefit from rescreening of serum sodium levels during acute periods of stress that demand "stress" GC dosing. This will permit treatment and/or increased vigilance for ensuing permanent DI.

The frequency of elevated blood pressure in obese minority youth.

In this study, 167 obese persons were recruited (45 African Americans, 122 Caribbean Hispanic persons), with a mean age of 14.6+/-2.1 years, a mean body mass index (BMI) of 38+/-7.5 kg/m(2), and mean BMI Z-score of 2.47+/-0.36; 31 nonobese youth were recruited as controls (7 African Americans, 24 Caribbean Hispanic persons), with a mean age of 14.6+/-2.1 years, a mean BMI of 20+/-2.8 kg/m(2), and a mean BMI Z-score of -0.08+/-0.87. The objective was to assess the frequency of elevated blood pressure in obese minority youth. Weight, height, blood pressure (BP), and various biochemical markers were measured in each participant. Overall, 31% of the obese patients had elevated BP, compared with 3% of the control participants. Obese persons with elevated BP had significantly higher BMI, BMI Z-scores, and hemoglobin A1c levels. The frequency of elevated BP and the degree of systolic BP elevation increased with increasing BMI Z-score. Elevated BP was 10 times more frequent in obese minority youth, emphasizing the importance of screening for hypertension in this high-risk population.

Criteria for oral glucose tolerance testing of obese minority youth.

AIM: To identify those obese minority youth at greatest risk for having an abnormal oral glucose tolerance test (OGTT) indicating impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM2). STUDY DESIGN AND METHODS: 167 children, who met the ADA criteria for T2DM screening, underwent an OGTT. Logistic regression models were derived for girls, boys, and both. Based on significant variables, algorithms yielding 100% sensitivity were derived to identify candidates for screening. RESULTS: 12% of children screened had an abnormal OGTT. Girls who met the algorithm criteria for screening (HOMA > 4.5) had an abnormal OGTT with a sensitivity of 100% (95% confidence interval [CI] 0.988-1.0) and specificity of 53.7% (95% CI 0.41-0.648). Boys who met the algorithm screening criteria (HOMA >13, or HbAlc > 5.8%, or total cholesterol > 200 mg/dl) had an abnormal OGTT with a sensitivity of 100% (95% CI 0.979-1.000) and specificity of 76.6% (95% CI 0.632-0.849). The model was validated using a large patient sample, yielding similar results. CONCLUSIONS: In obese pubertal minority youth meeting the ADA criteria for DM2 screening, these algorithm screening criteria can be useful in identifying those at risk youth who should undergo an OGTT.

Unique deletion in exon 5 of SHOX gene in a patient with idiopathic short stature.

BACKGROUND/AIM: It is known that haploinsufficiency for the SHOX gene (short-stature homeobox gene on the X chromosome) is responsible for short stature in Turner syndrome and Leri-Weill dyschondrogenesis, and it has been reported that it is responsible for upwards of 1 in 50 cases of idiopathic short stature. SHOX haploinsufficiency is also associated with various radiographic abnormalities, such as coarse trabecular pattern, short metacarpals/metatarsals with metaphyseal flaring, altered osseous alignment at the wrist, radial/tibial bowing, triangularization of the radial head, abnormal tuberosity of the humerus, and an abnormal femoral neck. Shortening and bowing of the radius and dorsal dislocation of the distal ulna characterize the Madelung deformity. These characteristic findings led us to do a study assessing the predictive value of certain radiographic features in association with genetic markers of idiopathic short stature. METHODS: Here we describe a case of a Hispanic male with idiopathic short stature and Madelung deformity with a novel mutation in the SHOX gene. RESULTS: Additional studies revealed a strong family history of short stature and the same SHOX mutation segregating from the mother. CONCLUSION: This case resulted in the description of a novel mutation in exon 5 (M202delA) and suggests the importance of screening for SHOX mutations in patients with idiopathic short stature with subtle radiographic abnormalities, including the components of the Madelung deformity in their bone age films.

Management of hypertension in children and adolescents with the metabolic syndrome.

Because elevated blood pressure is one of the defining criteria of the metabolic syndrome, treatment of hypertension will be required in many, if not most, children and adolescents diagnosed with the metabolic syndrome. This review highlights several aspects of the approach to treatment of hypertension in young patients with the metabolic syndrome, including the definition of hypertension, use of nonpharmacologic measures, indications for instituting antihypertensive medications, and the potential adjunctive role that insulin-sensitizing agents may play in blood pressure reduction. The choice of antihypertensive agent is also discussed, along with consideration of the diabetogenic effects of various classes of antihypertensive agents. Consideration of all of these issues is important in achieving blood pressure control in children and adolescents with the metabolic syndrome, as appropriate treatment may help to forestall the development not only of type 2 diabetes but also of the cardiovascular disease that is frequently already present at the time of diagnosis of type 2 diabetes in adults.