A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome


Autoři: Virginia Kimonis aff001;  Abhilasha Surampalli aff001;  Marie Wencel aff001;  June-Anne Gold aff001;  Neil M. Cowen aff003
Působiště autorů: Division of Genetics and Genomic Medicine, Department of Pediatrics, Univ. of California-Irvine School of Medicine, Orange, California, United States of America aff001;  Department of Pediatrics, Loma Linda University Medical School, Loma Linda, California, United States of America aff002;  Soleno Therapeutics, Redwood City, California, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221615

Souhrn

Introduction

Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS.

Method

This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period.

Results

Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide.

Conclusion

DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

Klíčová slova:

Adipose tissue – Adverse events – Drug therapy – Edema – Cholesterol – Neurons – Prader-Willi syndrome – Diazo compounds


Zdroje

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PLOS One


2019 Číslo 9

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