In a 16-week randomized withdrawal study of 77 individuals with Prader-Willi syndrome (PWS), discontinuation to placebo led to a statistically significant worsening on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) versus continued VYKAT XR (diazoxide choline extended-release) treatment (P=0.0022). The placebo cohort gained more weight and had greater BMI z-score increases than those maintained on drug (LS mean weight difference -1.6 kg; 95% CI -3.1, -0.1; LS mean BMI z-score difference -0.09; 95% CI -0.17, -0.01). CGI-S and CGI-I trended in favor of active treatment but did not reach significance. Adverse events were similar between arms; there were no serious adverse events in the VYKAT XR arm and no discontinuations due to adverse events in either arm.
The core development is peer-reviewed publication of the C602 randomized withdrawal period (RWP) study in the Journal of Clinical Endocrinology and Metabolism. The RWP enrolled participants who had completed prior placebo-controlled and long-term open-label Phase 3 studies, randomizing them 1:1 to continue VYKAT XR or switch to placebo for 16 weeks. This study complements a broader Phase 3 program encompassing 127 participants and over 400 patient-years of exposure, which underpinned FDA approval of VYKAT XR in March 2025 as the first treatment indicated for hyperphagia in PWS.
Strategically, publishing an enriched, post-approval, randomized withdrawal dataset serves multiple purposes: it reinforces durability and dependence on continuous therapy in a chronic, behaviorally mediated symptom domain; it anchors payer and guideline discussions around a validated PRO (HQ-CT) that shows clear deterioration off therapy; and it addresses the perennial rare-disease evidence gap with controlled data beyond the initial pivotal readout. The choice of an RWP design, common in maintenance settings and feasible in small populations, trades off against potential enrichment bias but delivers a clean signal on maintenance of effect and clinical consequences of withdrawal, supported by convergent metabolic measures. The non-significant CGI trends highlight the operational reality that caregiver- and clinician-anchored global scales may be less sensitive than disease-specific PROs in short maintenance windows.
For sites and CROs, the data underscore a practical trial template for neurobehavioral rare diseases: ePRO-heavy capture of HQ-CT, centralized rater training for global scales, and longitudinal follow-up transitioning into withdrawal to demonstrate necessity of ongoing therapy. Operationally, an oral, once-daily therapy reduces visit intensity but requires consistent monitoring for hyperglycemia and edema—manageable within standard endocrine workflows yet material for protocol design and safety surveillance. For sponsors, the publication validates HQ-CT as a decision-grade endpoint and may inform endpoint selection and enrichment strategies in adjacent indications. Regulators and HTAs gain controlled evidence of both symptom and weight trajectory impacts, informative for labeling nuance and access policies. Vendors supporting eClinical data capture and caregiver engagement should anticipate increased demand for robust, remote PRO infrastructure in PWS and similar populations.
Next, watch for how post-approval evidence is operationalized: real-world outcomes to quantify adherence-dependent effectiveness, metabolic safety in broader use, and caregiver burden metrics that could influence payer criteria. Ex-US regulatory paths may lean on the RWP dataset, but additional pragmatic or registry-based evidence could be necessary to satisfy European HTA expectations around quality-of-life and resource utilization. Clinically, questions remain on long-term durability beyond 16 weeks of maintenance, the time course of relapse on withdrawal, and the consistency of effect across age strata, severe obesity, and glycemic risk profiles. For development teams, the signal here will likely accelerate adoption of randomized withdrawal or crossover designs, tighter PRO operationalization, and hybrid site/remote models to capture sensitive behavioral endpoints without inflating trial burden.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
