Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

The association between depression symptom endorsement and glycemic outcomes in adolescents with type 1 diabetes.

OBJECTIVE: The prevalence of depression among adolescents with type 1 diabetes is estimated to be 2-3 times higher than in the general population. In adults with type 1 diabetes and depression, short-term outcomes are worse compared to individuals just diagnosed with type 1 diabetes. This study aims to determine if depressive symptom endorsement is associated with glycemic outcomes and short-term complications in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Analysis was conducted using electronic medical records from the T1D Exchange Quality Improvement Collaborative. Adolescents with type 1 diabetes, aged 12-18, receiving treatment in a diabetes clinic who had been screened for depression with the PHQ-9 between 2016 and 2018 were eligible for inclusion. Individuals must have also had HbA1c data available from the day of depression screening and from 10 to 24 weeks after screening; the final sample size was 1714. RESULTS: Almost 30% of adolescents endorsed mild or greater (PHQ-9 ≥ 5) depressive symptoms. Endorsement of mild or greater depressive symptoms was associated with an 18% increased risk of an HbA1c ≥7.5% and a 42% increased risk of an HbA1c ≥9.0% on the day of screener administration. Depressive symptom endorsement was also associated with an 82% increased risk for DKA. CONCLUSIONS: This study suggests that depression symptoms are associated with an increased risk for elevated HbA1c and short-term complications. With the rising incidence of type 1 diabetes in youth, routine screening, and appropriate management of depression is needed.

A Quality Improvement Project to Implement Choking Prevention and First Aid Education in Prader-Willi Syndrome Caregivers.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder characterized by hypotonia and hyperphagia. Consequently, individuals with PWS are at high risk of choking, and choking is a leading cause of morbidity and mortality. The aim of this quality improvement (QI) project is to provide choking prevention and first aid education from 0% to 80% of PWS caregivers seen in a multidisciplinary PWS clinic, and to assess the effectiveness of this education program. A QI initiative was developed to standardize and implement choking prevention and first aid education for PWS caregivers. Using a Likert scale, pre- and post-education assessments were conducted to measure caregiver (1) awareness of the PWS choking risk, (2) self-reported knowledge of choking prevention strategies, and (3) comfort in providing choking first aid. The American Heart Association Family and Friends® CPR (Dallas, TX, USA) curriculum was utilized. Education was provided during a regularly scheduled PWS clinic appointment. At project conclusion, 45/52 (87%) of PWS caregivers received education. A post-education assessment revealed an improvement in PWS caregivers' awareness of choking risk, self-reported knowledge of choking prevention strategies, and comfort in providing choking first aid. This QI project supports a practice change to implement choking prevention and first aid education as standard process within our PWS clinic.

Quality Improvement in Diabetes Care: A Review of Initiatives and Outcomes in the T1D Exchange Quality Improvement Collaborative.

Despite immense strides in therapeutic advances, clinical outcomes continue to be less than ideal for people with type 1 diabetes. This discrepancy has prompted an outpouring of quality improvement (QI) initiatives to address the medical, psychosocial, and health equity challenges that complicate ideal type 1 diabetes care and outcomes. This article reviews a framework for QI in diabetes care that guided the development of the T1D Exchange Quality Improvement Collaborative to improve care delivery and health outcomes in type 1 diabetes. Evaluation of the methodology, outcomes, and knowledge gained from these initiatives will highlight the importance of continued QI initiatives in diabetes care.

The Type 1 Diabetes Composite Score: An Innovative Metric for Measuring Patient Care Outcomes Beyond Hemoglobin A1c.

INTRODUCTION: Patient outcomes resulting from optimal type 1 diabetes (T1D) care have historically focused on driving a single metric, hemoglobin A1c. Our objectives were to design, build, and launch an aggregate clinical indicator that comprehensively reflects patient management status beyond hemoglobin A1c alone. This project aimed to show proof of principle that an aggregate score comprised of T1D outcome metrics could be built to track quality performance. METHODS: We established an electronic medical record-based diabetes registry and utilized its population health modules to design and build this diabetes care metric. Elements representing optimal diabetes management, as defined by current guidelines and expert opinion, were identified. Nine elements fall into categories of management tools, care assessments, and complications risk. The Type 1 Diabetes Composite Score (T1DCS) aggregates these outcome measures to reflect the overall diabetes care status for each patient. Higher scores suggest better management and overall improved patient health. RESULTS: We launched this metric build in November 2018 and applied the scoring to our T1D population (≈1,900 patients). The T1DCS quickly provides a summary of current diabetes management status. T1DCS viewed over the registry cohort demonstrates a normal distribution, and scores improved from March to September 2019, reflecting better care and outcomes, and illustrating the potential to track program effectiveness. CONCLUSIONS: The T1DCS is a useful metric to evaluate the clinical status of T1D patients, assess the capability of a clinical program to achieve optimal diabetes outcomes, identify patient diversity opportunities, and document outcome improvement as a novel comprehensive quality measure.

The diabetes care index: A novel metric to assess delivery of optimal type 1 diabetes care.

OBJECTIVES: The American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have outlined standards for best practices in providing optimal diabetes care to children with type 1 diabetes (T1D). Our objectives were to design a metric that evaluated delivery of optimal diabetes care and to use this metric to drive improvement within our diabetes program. METHODS: Using published guidelines, we identified 11 elements of optimal diabetes care that should be reliably delivered at our institution as standard-of-care. We utilized our electronic medical record to aid in data collection and to notify staff when to deliver specific care elements (eg, lipid collection, depression screening, etc.). We designed the T1D Care Index (T1DCI), a metric which aggregates missed opportunities to deliver elements of optimal diabetes care over a given period into a cumulative score, with a lower T1DCI reflecting better care delivery and improved program performance. RESULTS: Tracking the T1DCI permitted recognition of areas to focus on quality improvement efforts, guided interventions to improve processes for care delivery, and helped determine the allocation of time and resources. Interventions resulted in improvement of care delivery across some elements of care. Overall, we observed a 26% reduction in the T1DCI after 12 months of utilization. CONCLUSIONS: The T1DCI is a powerful metric to evaluate the ability of our diabetes program to standardize, quantify, and monitor delivery of optimal diabetes care to children with T1D, and to drive our program toward zero missed opportunities for quality care delivery.

No central adrenal insufficiency found in patients with Prader-Willi syndrome with an overnight metyrapone test.

Background Individuals with Prader-Willi syndrome (PWS) have hypothalamic dysfunction and may have central adrenal insufficiency (CAI). The prevalence of CAI in PWS remains unknown. Methods Twenty-one subjects with PWS aged 4-53 years underwent a low dose adrenocorticotropic hormone (ACTH) stimulation test (LDAST) (1 µg/m2, maximum 1 µg) followed by an overnight metyrapone test (OMT). Metyrapone (30 mg/kg, maximum 3 g) was administered at 2400 h. Cortisol, 11-deoxycortisol (11-DOC) and ACTH levels were collected the following morning at 0800 h. OMT was the standard test for comparison. Peak cortisol ≥15.5 µg/dL (427.6 nmol/L) on LDAST and 0800 h 11-DOC ≥7 µg/dL (200 nmol/L) on OMT were classified as adrenal sufficiency. Results Twenty subjects had 0800 h 11-DOC values ≥7 µg/dL on OMT indicating adrenal sufficiency. One subject had an inconclusive OMT result. Six of the 21 (29%) subjects had peak cortisol <15.5 µg/dL on LDAST. Conclusions We found no evidence of CAI based on OMT, yet 29% of our PWS population failed the LDAST. This suggests that the LDAST may have a high false positive rate in diagnosing CAI in individuals with PWS. OMT may be the preferred method of assessment for CAI in patients with PWS.