Challenges and Considerations in Design of a Placebo-Controlled, Double-Blind, Randomized-Withdrawal Study Evaluating the Efficacy and Safety of JZP-258 for the Treatment of Idiopathic Hypersomnia

No treatment is approved for idiopathic hypersomnia (IH). A retrospective chart review (Leu-Semenescu, et al. Sleep Med. 2016;17:38-44) demonstrated effectiveness of sodium oxybate (SXB) for the treatment of IH and noted individualized dosing strategies in patients with IH. A clinical trial was designed to assess efficacy/safety of JZP-258, a novel oxybate candidate with 92% less sodium than SXB, for the treatment of IH (NCT03533114). A placebo-controlled, double-blind, randomized-withdrawal design was selected to minimize placebo exposure, enable individualized titration of JZP-258 treatment to address disease heterogeneity, optimize efficacy and safety, and ensure optimal sleep duration. Ongoing treatment with wake-promoting agents or stimulants was allowed. In an open-label titration/optimization period (10–14 weeks), JZP-258 treatment is initiated (≤2.25 g twice nightly, ≤3.0 g once nightly, or SXB regimen if taking SXB at study entry) and titrated to an optimal regimen (total nightly dose ≤9 g; single-dose administration, ≤6 g; 1–3 dose administrations/night). After a stable-dose period, participants are randomized to placebo or JZP-258, followed by an open-label safety period. Efficacy measures include Epworth Sleepiness Scale, Patient Global Impression of Change, IH Severity Scale, and assessments of sleep inertia and sleep duration. This trial was designed specifically to enable individualized dosing to optimize treatment, including unequal division of the total nightly dose and administration of a single dose ≤6 g, and to allow for once- or twice-nightly dosing at treatment initiation, and thrice-nightly dosing if clinically indicated, to ensure optimal sleep duration. Safety is monitored throughout. Enrollment is complete (N=154).