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

2023; Oxford University Press; Volume: 108; Issue: 7 Linguagem: Inglês

10.1210/clinem/dgad014

1945-7197

Jennifer Miller, Evelien Gevers, Nicola Bridges, Jack A. Yanovski, Parisa Salehi, Kathryn Obrynba, Eric I. Felner, Lynne M. Bird, Ashley H. Shoemaker, Moris Angulo, Merlin G. Butler, David A. Stevenson, Jennifer Abuzzahab, Timothy Barrett, Melissa Lah, Elizabeth Littlejohn, Verghese Mathew, Neil Cowen, Anish Bhatnagar, Urmi Das, Amy Fleischman, Anthony P. Goldstone, Katerina Harwood, Prof Anthony Holland, Virginia Kimonis, Shawn E. McCandless, Lori Anne Schillaci, Mohammed Shaikh, Heidi Shea, David Viskochil, John Wilding,

Epigenetics and DNA Methylation

Abstract 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.