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Clinical Trial
. 2023 Jun 16;108(7):1676-1685.
doi: 10.1210/clinem/dgad014.

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

Jennifer L Miller  1 , Evelien Gevers  2 , Nicola Bridges  3 , Jack A Yanovski  4 , Parisa Salehi  5 , Kathryn S Obrynba  6 , Eric I Felner  7 , Lynne M Bird  8 , Ashley H Shoemaker  9 , Moris Angulo  10 , Merlin G Butler  11 , David Stevenson  12 , Jennifer Abuzzahab  13 , Timothy Barrett  14 , Melissa Lah  15 , Elizabeth Littlejohn  16 , Verghese Mathew  17 , Neil M Cowen  18 , Anish Bhatnagar  18 ; DESTINY PWS Investigators
Collaborators, Affiliations
Clinical Trial

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

Jennifer L Miller et al. J Clin Endocrinol Metab. .

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.

Trial registration: ClinicalTrials.gov NCT03440814.

Keywords: DCCR; Prader-Willi syndrome; hyperphagia.

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Conflict of interest statement

Conflict of Interest N.C. and A.B. are employed by Soleno Therapeutics and own stock in the company. N.C. is an inventor on patents assigned to Soleno Therapeutics. The institution of J.L.M., E.G., N.B., J.A.Y., P.S., K.S.O., E.I.F., L.M.B., A.H.S., M.A., M.G.B., D.S., J.A., T.B., M.L., E.L., and V.M. received funding from Soleno to support the conduct of the clinical trial. L.M.B. reports that the support provided to the organization she is associated with for the conduct of the clinical trial also included some salary support. E.G. reports receipt of lecturing and consulting fees from Soleno. J.A.Y. reports grant support from Soleno Therapeutics and from Rhythm Pharmaceuticals for obesity-related projects, and material support for research from Hikma Pharmaceuticals and Versanis-Bio.

Figures

Figure 1.
Figure 1.
CONSORT diagram for the DESTINY PWS (C601) study.
Figure 2.
Figure 2.
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) change from baseline to week 13 for the intent-to-treat population (ITT), the preplanned analysis of participants with baseline HQ-CT score greater than median (>22) (BL HQ_CT > 22) and the post hoc analysis of HQ-CT data collected before March 1, 2020 (ITT pre-COVID). Diazoxide choline extended-release tablet (DCCR) in green, placebo in light blue.
Figure 3.
Figure 3.
Exposure-Response analysis for Hyperphagia Questionnaire for Clinical Trials) (HQ-CT change from baseline at week 13. Cmin, average trough concentration. Each point represents end-of-study results for one study participant. Placebo points are jittered for visualization purposes. The blue line is a linear regression fit. The shaded region represents 90% CI. The P value is the statistical significance level for the slope of the linear fit using a z test. Source: er-analysis.r.
Figure 4.
Figure 4.
Exposure response analysis for leptin change from baseline at week 13. Cmin, average trough concentration; HQ-CT, Hyperphagia Questionnaire for Clinical Trials. Each point represents end-of-study results for one study participant. Placebo points are jittered for visualization purposes. The blue line is a linear regression fit. The shaded region represents 90% CI. The P value is the statistical significance level for the slope of the linear fit using a z test. Source: er-analysis.r.
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References

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