Dear Editor,

We read with interest “Implications of Oxybate Dosing Regimen for Sleep, Sleep Architecture, and Disrupted Nighttime Sleep in Patients with Narcolepsy: A Commentary,” by Rosenberg et al. [1], which was published recently in Neurology & Therapy. The authors examine the impact of different sodium oxybate (SXB) dosing regimens on disrupted nighttime sleep (DNS) in patients with narcolepsy by comparing published data from five clinical trials: three trials of immediate-release (IR) SXB in adults, one trial of IR SXB in pediatrics, and one trial of extended-release SXB. IR SXB (Xyrem®) and IR calcium/magnesium/potassium/sodium oxybates (Xywav®) must be taken at bedtime, with a second dose administered 2.5–4 h later, while extended-release SXB (ON-SXB; LUMRYZ™) is taken once at bedtime.

While the authors correctly state that direct comparisons between IR SXB and ON-SXB cannot be made because of lack of head-to-head trials, the title and much of the discussion do directly compare and draw inferences across these disparate trials. Given that one regimen requires a middle-of-the-night dose of medication, a blinded head-to-head trial is not feasible. Therefore, if clinicians and researchers want to consider data from respective trials, it is imperative that accurate data are cited.

However, the authors cite nine discrete inaccuracies from the REST-ON trial that merit correction in Table 2 of the publication, as well as throughout the text. Specifically, the authors comingle REST-ON trial data for both the modified intent-to-treat (mITT) population (defined as all participants randomized to treatment with at least one efficacy measurement after receiving either the 6 g ON-SXB dose or placebo) and stimulant use subgroup (participant subgroup within the mITT population) while comparing IR SXB data from the mITT population of their respective studies.

Notably, the observed differences in the subgroup data presented by Rosenberg et al. [1] are lower than the correct mITT population data that should have been cited from Roth et al. [2]:

  • Greater reductions from baseline in sleep stage shifts observed in the mITT population compared with the cited stimulant use subgroup (least squares mean difference, – 11.0 [6 g], – 17.7 [7.5 g], – 22.6 [9 g] vs – 9.0 [6 g], – 16.2 [7.5 g], – 21.1 [9 g]);

  • Greater reductions from baseline in nocturnal arousals in the mITT population compared with the cited stimulant use subgroup (– 11.3 [6 g], – 19.4 [7.5 g], – 23.7 [9 g] vs – 6.4 [6 g], – 18.8 [7.5 g], – 21.3 [9 g]);

  • Greater increases from baseline in patient-reported sleep quality in the mITT population compared with the cited stimulant use subgroup (7.0 [6 g], 9.9 [7.5 g], 10.4 [9 g] vs 5.4 [6 g], 7.4 [7.5 g], 6.5 [9 g]).

While analysis of cross-study comparisons should always be interpreted with caution given the differences in methodology, it is critical that data from similar analytic populations be used. Roth et al. [2] clearly delineate the prespecified endpoints for sleep stage shifts, nocturnal arousals, and sleep quality in the mITT population in Figs. 1, 2, and 3. The stimulant use subgroup data cited by Rosenberg et al. [1] may lead readers to undervalue the efficacy of ON-SXB.

Stimulants are often prescribed in conjunction with oxybates; in the prior oxybate studies, as well as that of ON-SXB, concomitant stimulant use was reported in approximately 56–78% of participants [2,3,4]. To our knowledge, data examining efficacy for DNS and daytime symptoms of narcolepsy based upon presence or absence of concomitant stimulant use have only been published for ON-SXB.

Rosenberg et al. [1] also speculate that the second, middle-of-the-night dose of IR SXB may have clinically relevant effects due to increased exposure to oxybate and increased slow-wave sleep (SWS) in the second half of the night. However, awakenings from SWS may contribute to sleep inertia, as reduced cognitive performance has been observed following waking from SWS compared to lighter sleep [5]. ON-SXB, which contains both immediate-release and controlled-release particles, provides an early maximum concentration, with a slow decline over the nocturnal sleep period. Theoretically, this pharmacokinetic profile is more likely to induce more SWS in the first half of the night [6, 7].