Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.

BACKGROUND: The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. METHODS: These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. INTERPRETATION: Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. FUNDING: Rhythm Pharmaceuticals.

Delayed diagnosis of proopiomelanocortin (POMC) deficiency with type 1 diabetes in a 9-year-old girl and her infant sibling.

BACKGROUND: Proopiomelanocortin (POMC) protein, encoded by the POMC gene, is the precursor of adrenocorticotropic hormone (ACTH) that is released from the anterior pituitary gland. Homozygous mutations in the POMC gene is associated with hyperphagia, severe and early-onset obesity, adrenal insufficiency, hypopigmentation of the skin and red hair. CASE PRESENTATION: A 9-year-old girl from a consanguineous family of Iraqi origin was diagnosed with type 1 diabetes. She also had a tall stature. Her laboratory assessment showed low cortisol and ACTH concentrations, normal renin and poor response to ACTH stimulation. Genetic testing revealed a novel biallelic mutation in the POMC gene. Her sibling who had severe obesity and central adrenal insufficiency was found to be a carrier of the same mutation. Both siblings had alabaster-colored skin and brown hair. CONCLUSIONS: POMC deficiency results in significant morbidity due to obesity, and it is also a potentially life threatening disease because of adrenal insufficiency. Therefore any suggestive symptom or sign of POMC deficiency warrants detailed investigations.

Evaluating the Impact of Clinical Decision Tools in Pediatric Acute Gastroenteritis: A Population-based Cohort Study.

OBJECTIVE: Acute gastroenteritis (AGE) is a leading cause of pediatric emergency department (ED) visits. Despite evidence-based guidelines, variation in adherence exists. Clinical decision tools can enhance evidence-based care, but little is known about their use and effectiveness in pediatric AGE. This study sought to determine if the following tools-1) pathways/order sets, 2) medical directives for oral rehydration therapy (ORT) or ondansetron, and 3) printed discharge instructions-are associated with AGE admission and ED revisits. METHODS: This was a retrospective population-based cohort study of all children 3 months-18 years with an AGE ED visit in Ontario, Canada, from 2008 to 2010, using linked survey and health administrative databases. Logistic regression models associating clinical decision tools (CDTs) with hospitalizations and revisits controlling for hospital and patient characteristics were employed. RESULTS: Of the 57,921 patient visits during the study period, there were 2,401 hospitalizations (4.2%). A total of 55,520 patients were discharged from the ED, with 2,378 (4.3%) experiencing a 72-hour return visit. In adjusted models, none of the tools were significantly associated with admission. Medical directive for ORT was associated with lower return visit rates (adjusted odds ratio [aOR] = 0.86, 95% confidence interval [CI] = 0.79-0.94] and printed discharge instructions with higher return visits (aOR = 1.33, 95% CI = 1.08-1.65); pathways/order sets and medical directives for ondansetron had no association. CONCLUSIONS: Admissions in children with AGE are not associated with the presence of CDTs. While ORT medical directives are associated with lower ED revisits, printed discharge instructions have the opposite effect. The simple presence/absence of decision support tools does not guarantee improved clinical outcomes.

A survey of emergency department resources and strategies employed in the treatment of pediatric gastroenteritis.

OBJECTIVES: Although leading organizations have developed gastroenteritis management guidelines, little is known about emergency department (ED) use of clinical tools to improve outcomes. Our objective was to describe pediatric gastroenteritis clinical decision tools employed in EDs in the province of Ontario and to determine if a greater number of clinical decision tools are employed in academic, high-volume institutions staffed primarily by emergency medicine (EM)-trained physicians. METHODS: A cross-sectional, Internet-based survey was distributed in the summer of 2010 to medical directors and managers of Ontario EDs. Domains included patient population, general resources, and gastroenteritis-specific strategies. Copies were requested of all gastroenteritis-specific strategies to enable a content review. RESULTS: A total of 133 (83%) of 160 eligible participants responded. Practice guidelines, pathways, or order sets; medical directives; and printed discharge instructions were reported to be in use at 38 of the 133 (29%), 69 of 133 (52%), and 105 of 133 (79%) of the responding institutions, respectively. Oral rehydration therapy (ORT) is routinely initiated at triage in only 51 of the 133 of the EDs (38%). High-volume institutions are more likely to have clinical practice guidelines, pathways, or order sets (p = 0.001) than low- and medium-volume EDs. Physician training in EM was associated with the presence of medical directives for nursing administration of antiemetics and antipyretics (p = 0.04). Review of clinical practice guidelines, pathways, and order sets showed that only six of 27 gastroenteritis-specific strategies reviewed were correctly classified, and 20 (74%) met prespecified quality criteria. CONCLUSIONS: Clinical decision tools designed to improve pediatric gastroenteritis management are not commonly implemented. Such strategies are more common in high-volume EDs and those staffed primarily by physicians with EM training.

A survey of Canadian medical student attitudes towards the ethics of pediatric clinical trials: are they different from Canadian and British health care professionals?

BACKGROUND: Due to ethical concerns and constraints inherent to research in children, the conduct of clinical trials in children has often been difficult. The views of medical professionals and trainees towards conducting clinical trials in children have been largely unexplored and are potentially important towards working to increase the number of appropriate trials conducted in children. OBJECTIVE: To explore the views of Canadian medical school trainees towards paediatric clinical trials and to compare these views with that of an earlier pilot study conducted amongst Canadian and British health care professionals. METHODS: Participants were given a questionnaire which consisted of direct questions as well as scenarios with ethical dilemmas. Responders were asked to state whether they would enter children in the trial documented in the scenario and to justify their reasons. RESULTS: 89 questionnaires were collected (74% response rate). 42% had formal teaching regarding paediatric ethical dilemmas but only 2% had formal teaching on pharmaceutical testing in children. The students were divided on whether children should only participate in trials where they receive direct benefit. Most students (85%; 95% CI: 77% to 91%) were comfortable with non-inferiority trials even with post-hoc consent. Only a third (33%; 95% CI: 24% to 43%) agreed with the use of placebo in an analgesia trial. CONCLUSION: Teaching on the ethics of paediatric clinical trials still appears to be lacking amongst medical trainees. However, there does seem to be increased willingness on the part of trainees compared to practicing medical professionals in enrolling children in clinical trials.

Interlocking oppressions: the effect of a comorbid physical disability on perceived stigma and discrimination among mental health consumers in Canada.

People living with mental health problems often face stigma and discrimination; however, there is a lack of research that examines how comorbid conditions affect this perceived stigma. This study sought to determine whether people who have a comorbid physical and psychiatric disability experience more stigma than those with only a psychiatric disability. It also looked at how perceived stigma and discrimination affect physical and mental health. A secondary analysis on data from interviews with 336 former and current clients of the mental health system in a mid-size Canadian city in 2005 was performed. Of these, 203 (60.4%) reported they had a psychiatric disability, 112 (33.0%) reported that they had a physical disability, with 74 reporting both a psychiatric and a physical disability. People with a self-reported psychiatric disability and a self-reported comorbid physical disability faced more overall perceived discrimination/stigma (P = 0.04), than those with a psychiatric disability alone. Perceived discrimination/stigma was positively correlated with psychiatric problem severity (P = 0.02), and negatively correlated with self-rated general health (P < 0.001), physical condition (P < 0.001), emotional well-being (P < 0.001) and life satisfaction (P < 0.001). These results bring to light the aggravating effect of a physical disability on the perceived stigma for those living with a mental illness, and also strengthen the knowledge that stigma and discrimination have a negative impact on health. Healthcare providers should recognise this negative impact and screen for these comorbid conditions. Policy-makers should take measures such as improving access to housing and employment services to help reduce stigma and discrimination against this particularly vulnerable group.