Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment

Maski, Kiran; Trotti, Lynn Marie; Kotagal, Suresh; Auger, R. Robert; Swick, Todd J.; Rowley, James A.; Hashmi, Sarah D.; Watson, Nathaniel F.

doi:10.5664/jcsm.9326

Cited by 51 publications

(17 citation statements)

References 110 publications

(362 reference statements)

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“…In contrast, in the 2002 twice-nightly SXB pivotal clinical trial, only the 9-g dose was statistically significant on EDS as measured by the ESS [ 33 ]. Newly released clinical practice guidelines from the American Academy of Sleep Medicine set a change from baseline compared to placebo of two or more minutes on the MWT, including the 95% CIs, as being the clinical significance threshold [ 34 , 35 ]; ON-SXB achieved this standard for all three doses evaluated ( Figure 3A ). This is the first randomized controlled trial that demonstrated the efficacy and safety of a 7.5-g dose of SXB; given that the efficacy was nearly comparable to the 9-g dose compared to placebo, this may afford confidence for clinicians and patients that a lower dose can be effectively used in practice.…”

Section: Discussionmentioning

confidence: 99%

Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy

Kushida

Shapiro

Roth

et al. 2021

Sleep

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Study Objectives To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial. Methods Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments. Results In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n=107) or placebo (n=105). For the 3 coprimary endpoints and Epworth Sleepiness Scale, all 3 doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement vs placebo (all P<0.001). For ON-SXB 9 g vs placebo, increase in mean sleep latency was 10.8 vs 4.7 min (LSMD [95% CI], 6.13 [3.52–8.75]), 72.0% vs 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76–11.23]), change in mean weekly number of cataplexy attacks was –11.5 vs –4.9 (LSMD [95% CI], –6.65 [–9.32 to –3.98]), and change in Epworth Sleepiness Scale was –6.5 and –2.7 (LSMD [95% CI], –6.52 [–5.47 to –2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis. Conclusions ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.

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Section: Discussionmentioning

confidence: 99%

Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy

Kushida

Shapiro

Roth

et al. 2021

Sleep

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“…A clinically meaningful response in cataplexy, defined as a reduction in WRC of at least 50%, was noted in 61% of pitolisant-treated patients at the last on-treatment assessment in HARMONY CTP; 76% of patients had a WRC reduction of at least 25%. The definitions of clinically meaningful response used in this analysis are consistent with clinical significance thresholds identified in the systematic literature review that supported the 2021 American Academy of Sleep Medicine clinical practice guideline on the treatment of central disorders of hypersomnolence [ 39 ].…”

Section: Discussionmentioning

confidence: 90%

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials

Watson

Davis²,

Zarycranski³

et al. 2021

CNS Drugs

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Background Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. Objective Analyses evaluated the time to onset of clinical response during treatment with pitolisant. Methods Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo. ResultsThe analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]). Conclusions Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy.

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“…At week 1, the mean ESS and IHSS scores decreased from baseline by 2.3 and 4.4 points, respectively, which is consistent with the established thresholds for a minimum within-person change (≥2 points for ESS [based on narcolepsy] and 4 points for IHSS [IH specific]). 16,21 Improvements in scores of the QoL measures FOSQ-10 and WPAI:SHP were also observed at the end of stable-dose treatment. Participants reached a stable dose of LXB in a median of 48.5 days; the median dose was 7 g/night, and the majority of participants were stable on a twice-nightly dosing regimen.…”

Section: Discussionmentioning

confidence: 94%

Efficacy and Safety of Lower-Sodium Oxybate in an Open-Label Titration Period of a Phase 3 Clinical Study in Adults with Idiopathic Hypersomnia

Thorpy¹,

Arnulf²,

Foldvary‐Schaefer³

et al. 2022

NSS

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Purpose To report the efficacy and safety of lower-sodium oxybate (LXB; Xywav ® ) during the open-label titration and optimization period (OLT) and stable-dose period (SDP) in a clinical study for the treatment of idiopathic hypersomnia. Patients and Methods Data were collected during treatment titration and optimization in a phase 3 randomized withdrawal trial in adults (18–75 years of age) with idiopathic hypersomnia who took LXB treatment (once, twice, or thrice nightly, administered orally) in the OLT (10–14 weeks), followed by the 2-week, open-label SDP. Endpoints included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change, Clinical Global Impression of Change, Functional Outcomes of Sleep Questionnaire (FOSQ)-10, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Results The safety population included 154 participants; the modified intent-to-treat population comprised 115 participants. During open-label treatment, mean (SD) ESS scores improved (decreased) from 15.7 (3.8) at baseline to 6.1 (4.0) at end of SDP, and IHSS scores improved (decreased) from 31.6 (8.3) to 15.3 (8.5). Improvements were also observed during OLT in each individual IHSS item and in FOSQ-10 and WPAI:SHP scores. Thirty-five (22.7%) participants discontinued during OLT and SDP, 22 (14.3%) due to treatment-emergent adverse events (TEAEs) during OLT and SDP. The most frequent TEAEs in the first 4 weeks were nausea, headache, dizziness, and dry mouth; TEAE incidence decreased throughout OLT and SDP (weeks 1–4, n = 87 [56.5%]; weeks 13–16, n = 39 [31.7%]). Conclusion During open-label treatment with LXB, participants showed clinically meaningful improvements in idiopathic hypersomnia symptoms and in quality of life and functional measures. TEAE incidence declined over LXB titration and optimization.

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Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment

Cited by 51 publications

References 110 publications

Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy

Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials

Efficacy and Safety of Lower-Sodium Oxybate in an Open-Label Titration Period of a Phase 3 Clinical Study in Adults with Idiopathic Hypersomnia

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