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.

A quality improvement project for managing hypocalcemia after pediatric total thyroidectomy.

Objectives Hypocalcemia following total thyroidectomy (TT) is relatively common. It may result in significant morbidity, prolonged hospital stay, and increased costs. Treatment with intravenous (IV) calcium gluconate may also carry significant risks. In pediatrics, management consensus guidelines are lacking. Methods At Phoenix Children's Hospital, a team of pediatric endocrinologists, surgeons and otolaryngologists developed a clinical pathway for patients undergoing TT. It was a Quality Improvement (QI) project with the primary aim of decreasing IV calcium gluconate use from a baseline of 68% to less than 40% over 15 months. Secondary aims included reducing hypocalcemia and length of hospitalization. Interventions included sending weekly pathway reminder emails, starting pre-operative calcium, and pathway implementation into the electronic health record. Results Twenty-seven patients underwent TT over 15 months. IV calcium gluconate use dropped to 48%. Hypocalcemia and length of hospitalization were 96% and 52.7 h (range 21.1-115.7) respectively. Pathway adherence improved after targeted interventions. Eleven (73%) of the 15 patients whose post-operative parathyroid hormone (PTH) nadir was below 15 pg/mL required IV calcium gluconate vs. two (17%) out of 12 with levels above this threshold. Conclusions Standardizing care allowed for objective outcome analysis. We learned that post-operative serum PTH level was the main risk factor for requiring IV calcium gluconate. Implementing the pathway as a QI project allows for revisions based on outcomes, ultimately resulting in a pathway that best utilizes our infrastructure to optimize care. Other pediatric institutions may face similar challenges and can potentially learn from our experience.

Endocrine and pubertal disturbances in optic nerve hypoplasia, from infancy to adolescence.

BACKGROUND: Endocrinologic abnormalities are a common co-morbidity in patients with optic nerve hypoplasia (ONH), however the impact on puberty is unknown. The purpose of this study was to examine rates of endocrine dysfunction and pubertal disturbances in a pediatric population of ONH. METHODS: A retrospective chart review was conducted on a cohort of children with ONH between January 2005 and March 2013. Endocrine dysfunction was determined based on laboratory evidence of hormone deficiency or hormone replacement. Pubertal disturbances were characterized based on presence of micropenis, tanner staging, menarche and hormone replacement. Pituitary abnormalities were classified using MRI findings. Descriptive statistics were used, and comparisons between groups were performed using the chi-square test. RESULTS: During the study period, 101 patients underwent an endocrine evaluation (median age: 2.3 years [0.76 - 6.5]). Hypopituitarism was present in 73% of patients with growth hormone deficiency (56%) and hypothyroidism (54%) being the most common. Pubertal disturbances (n = 19) were common; micropenis in 31% (13/42) of males and 2% with precocious puberty. Half of adolescents (n = 4/8) were diagnosed with gonadotropin deficiency. Patients with MRI pituitary abnormalities were more likely to have endocrine dysfunction than those without (p = 0.004). The sensitivity and specificity of MRI pituitary abnormalities for hypopituitarism was 54% and 92%, respectively. CONCLUSIONS: A significant proportion of children with ONH have endocrine dysfunction. The high frequency of pubertal disturbances in this study emphasizes the need for long-term monitoring of developing endocrinopathy. While pituitary gland abnormalities are a good predictor of endocrine dysfunction, a normal pituitary gland does not rule out endocrinopathy.