Characterization of Peripheral Edema in Individuals with Prader-Willi Syndrome During Long-term Administration of Diazoxide Choline Extended-Release Tablet (DCCR) Over 4.5 Years
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Authors
Shoemaker A.H.
Yanovski J.A.
Gevers E.F.
Obrynba K.S.
Lah M.
Salehi P.
Ballal S.
Perry J.
Huang M.
Miller, J. L.
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2025
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Objectives: To characterize peripheral edema in clinical trial participants with Prader-Willi Syndrome (PWS) during administration of diazoxide choline extended-release (DCCR) over 4.5 years. Method(s): PWS is a rare genetic neurobehavioral metabolic disorder characterized by hyperphagia. DCCR is an oral, once-daily medication under development for the treatment of patients with PWS who have hyperphagia. We analyzed data for participants who received DCCR across 2 Phase 3 studies (C601 - a randomized placebo-controlled trial, and C602 OLE - an open label extension trial to C601). The analyses included 125 participants who received DCCR in either study. At each study visit, examination of the lower extremities was performed with digital pressure and edema was graded on a scale of 1+ to 4+ based on degree and duration of pitting. Time to first onset of peripheral edema adverse event (AE) was estimated from the product-limit (Kaplan-Meier) method. Result(s): Mean duration of DCCR exposure was 131.5 weeks, and maximum duration was 237.3 weeks. 52% of participants exceeded 3 years of exposure. Before start of DCCR, 16.8% of participants had a medical history of (peripheral) edema. Peripheral edema occurred intermittently as assessed by both physical examination and AEs. With the exception of the Week 13 visit, when 2 participants (1.6%) exhibited grade 3+ pitting edema on physical examination, at all other visits through Week 156, severity of peripheral edema was mild (1+ to 2+ pitting edema) and >90% of participants at each visit did not have peripheral edema on physical examination. Forty-six participants (36.8%) reported AEs related to peripheral edema at any time during the study. Most participants (44 participants; 35.2%) reported mild (Grade 1 or 2) peripheral edema. Two participants (1.6%) reported Grade 3 peripheral edema and no participants reported any Grade 4 or 5 events. In response to AEs related to peripheral edema, Investigators implemented DCCR dose reductions in 8.7% (4/46), dose interruptions in 6.5% (3/46), and new diuretics in 2.2% (1/46). Treatment discontinuation for peripheral edema was infrequent and occurred in 6.5% (3/46) of affected participants. Time to event analysis showed most participants with an AE related to peripheral edema first experienced the event early in treatment (within the first 6 months), with fewer having new events later. Specifically, 68.0% of participants remained event free at 6 months based on a Kaplan-Meier analysis. Conclusion(s): Administration of DCCR to patients with PWS was associated with peripheral edema in a minority of C601 + C602-OLE participants. When present, peripheral edema tended to occur early in treatment, was usually Grade 1 or 2, and infrequently resulted in study medication interruption or discontinuation. Overall, DCCR was well tolerated in the intended population.
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J.Endocr Soc.