EFFICACY IN IDIOPATHIC HYPERSOMNIA
XYWAV is the first & only FDA-approved treatment option for adult patients with Idiopathic Hypersomnia (IH)1,2
XYWAV was evaluated in the largest phase III study of an IH patient population to
date—a double-blind, placebo-controlled, randomized withdrawal, multicenter study of 154 adult patients with IH aged 19 to 75.1,3-5
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XYWAV has been evaluated across these key measures1:
- Epworth Sleepiness Scale (ESS)—Assesses excessive daytime sleepiness (EDS) or patient perceptions of likelihood they will fall asleep during usual daily activities.
See ESS data - Patient Global Impression of Change (PGIc)—Assesses patient perceptions of symptom change from "very much improved" to "very much worse."
See PGIc data - Idiopathic Hypersomnia Severity Scale (IHSS)—Assesses the severity and frequency of idiopathic hypersomnia symptoms, including excessive sleepiness, prolonged sleep duration, cognitive impairment, and sleep inertia.
See IHSS data
primary efficacy endpoint: efficacy in EXCESSIVE daytime sleepiness (as measured by ess)
Significant worsening of daytime sleepiness in patients randomized to placebo during the 2-week , double-blind, randomized withdrawal period1,6
Mean ESS score remained stable from the end of the SDP through the end of the
ESS score of 10 or below falls within the normative range of sleepiness.7
Limitations: Trial was not designed to demonstrate efficacy during the OTTP; all patients were taking active drug while dose was being titrated to individual optimized dose; no conclusions can be drawn about the effect of XYWAV during this period.
*LS mean difference between XYWAV and placebo in the change in ESS score from end of 2-week SDP to end of 2-week DB RWP8
DB RWP = Double-Blind, Randomized Withdrawal Period; ESS = Epworth Sleepiness Scale; LS = Least Squares; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.
See more ESS data:
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ESS score of 10 or below falls within the normative range of sleepiness.7
Limitations: Trial was only designed to evaluate efficacy during the
Of 113 patients who completed the
106 continued XYWAV in a 24-week open label extension.9
DB RWP = Double-Blind, Randomized Withdrawal Period; ESS = Epworth Sleepiness Scale; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.
XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time, and twice-nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice-nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later. At the start of the
Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The LS mean differences were obtained from ANCOVA models, with the change in ESS total score from the end of SDP to the end of
ANCOVA = Analysis of Covariance; DB RWP = Double-Blind, Randomized-Withdrawal Period; ESS = Epworth Sleepiness Scale; LS = Least Squares; SDP = Stable-Dose Period.
This is an exploratory sub-group analysis of the mITT, which included 24 patients with long sleep time and 91 patients without long sleep time. Long sleep time was clinician reported at study entry based on ICSD-II or ICSD-III criteria. Demographic and baseline characteristics were generally well balanced between groups, with the exception of region. The low number of participants with long sleep overall, and the imbalance between those with long sleep recruited in Europe and North America, may limit generalizability.11
Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The LS mean differences were obtained from ANCOVA models, with the change in ESS total score from the end of SDP to the end of
*Long sleep time was defined as ≥11 hours or more of sleep in 24 hours.11
ANCOVA = Analysis of Covariance; DB RWP = Double-Blind, Randomized-Withdrawal Period; ESS = Epworth Sleepiness Scale; ICSD = International Classification of Sleep Disorders;
Watch experts discuss ESS data
key secondary endpoint: patient perception of change in symptoms (as measured by pgic)
Significantly more patients reported worsening* of IH overall when randomized to placebo during the 2-week , double-blind, randomized withdrawal period1
Percentage of patients reporting worsening* IH overall at the end of the
of patients continuing treatment with XYWAV reported improvement† or no change in their overall idiopathic hypersomnia at the end of
*Worsening of idiopathic hypersomnia defined as "minimally, much worse, or very much worse" PGIc scores.1
†Improvement of idiopathic hypersomnia defined as "minimally, much, or very much improved" PGIc scores.9
DB RWP = Double-Blind, Randomized-Withdrawal Period; PGIc = Patient Global Impression of Change.
key secondary endpoint: efficacy in idiopathic hypersomnia symptom severity (as measured by ihss)
Significant worsening in IH symptom severity in patients randomized to placebo during the 2-week , double-blind, randomized withdrawal period1,6
Mean IHSS score remained stable from the end of the SDP through the end of the 2-week
Limitations: Trial was not designed to demonstrate efficacy during the OTTP; all patients were taking active drug while dose was being titrated to individual optimized dose; no conclusions can be drawn about the effect of XYWAV during this period.
*Estimated median difference between XYWAV and placebo in change in IHSS from end of SDP to end of DB RWP8
DB RWP = Double-Blind, Randomized Withdrawal Period; IHSS = Idiopathic Hypersomnia Severity Scale; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.
See more IHSS data:
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IHSS score of 22 is the best cutoff value for discriminating between untreated patients with IH and controls.12
Limitations: Trial was only designed to evaluate efficacy during the
Of 113 patients who completed the
106 continued XYWAV in a 24-week open label extension.9
DB RWP = Double-Blind, Randomized Withdrawal Period; IHSS = Idiopathic Hypersomnia Severity Scale; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.
XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once-nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time, and twice-nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice-nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later. At the start of the
Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The estimated median differences between treatment groups are from Hodges-Lehmann estimates. A separate model was used for each regimen.
DB RWP = Double-Blind, Randomized-Withdrawal Period; IHSS = Idiopathic Hypersomnia Severity Scale; SDP = Stable-Dose Period.
This is an exploratory sub-group analysis of the mITT, which included 24 patients with long sleep time and 91 patients without long sleep time. Long sleep time was clinician reported at study entry based on ICSD-II or ICSD-III criteria. Demographic and baseline characteristics were generally well balanced between groups, with the exception of region. The low number of participants with long sleep overall, and the imbalance between those with long sleep recruited in Europe and North America, may limit generalizability.11
Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The estimated median differences between treatment groups are from Hodges-Lehmann estimates. A separate model was used for each regimen.
*Long sleep time was defined as ≥11 hours or more of sleep in 24 hours.11
DB RWP = Double-Blind, Randomized-Withdrawal Period; ICSD = International Classification of Sleep Disorders; IHSS = Idiopathic Hypersomnia Severity Scale; mITT =
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XYWAV was evaluated in the largest phase III study of IH patient population to date1,3-5,9
The efficacy and safety of XYWAV was evaluated in a robust double‑blind, placebo‑controlled, randomized withdrawal, multicenter study of adults with idiopathic hypersomnia1
- Evaluated in adults: 154 patients, aged 19 to 75 (median age 39 years)
- Treatment background (at baseline): Trial included patients (N=154) who were taking wake-promoting agents (WPA) or stimulants only (53%), treatment-naive (43%), taking sodium oxybate plus a WPA or stimulant (3%), taking sodium oxybate only (1%)
- Dosing regimens: Participants took either a twice-nightly or a once-nightly regimen at the discretion of the clinician according to the clinical presentation of the each patient. Approximately 57% of patients continued taking a stable dose of stimulant along with XYWAV throughout the SDP and DB RWP1
- Baseline disease severity (based on CGI-S): Trial included patients (N=154) who were borderline to mildly ill (3%), moderately to markedly ill (77%), severely to extremely ill (20%)
- Sleep time* (at baseline): Trial included patients (N=154) with long sleep time and without long sleep time; 20% and 80%, respectively
- Over 6 months (204 days) mean exposure to XYWAV in safety population: Included titration, stable-dose period, randomized withdrawal period, and open-label extension
*Long sleep time based on ICSD-II or ICSD-III criteria.
CGI-S = Clinical Global Impression of Severity; DB RWP = Double-Blind, Randomized Withdrawal Period; ICSD = International Classification of Sleep Disorders; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.
References:
- XYWAV® (calcium, magnesium, potassium, and sodium oxybates). Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.
- FDA grants first of its kind indication for chronic sleep disorder treatment. News release. U.S. Food and Drug Administration; August 12, 2021. Accessed October 21, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-first-its-kind-indication-chronic-sleep-disorder-treatment.
- Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. Published online April 23, 2021. https://doi.org/10.5664/jcsm.9326
- A multicenter study of the efficacy and safety of JZP-258 in the treatment of idiopathic hypersomnia (IH) with an open-label safety extension. ClinicalTrials.gov identifier: NCT03533114. Updated June 11, 2021. Accessed October 21, 2022. https://clinicaltrials.gov/ct2/show/NCT03533114
- Sodium oxybate in idiopathic hypersomnia (SODHI). ClinicalTrials.gov identifier: NCT03597555. Updated February 12, 2021. Accessed September 21, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03597555
- Data on File (XYW-2021-040). Palo Alto, CA: Jazz Pharmaceuticals, Inc.
- Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545.
- Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study. Lancet Neurol. 2022;21(1):53-65.
- Dauvilliers, Y, Arnulf I, Foldvary-Schaefer N, et al. Placebo-controlled, double-blind, randomized withdrawal study of lower-sodium oxybate in adults with idiopathic hypersomnia. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
- Arnulf I, Morse AM, Chandler P, Parvataneni R, Chen D, Dauvilliers Y. Efficacy and safety of once- and twice-nightly dosing of lower-sodium oxybate in adults with idiopathic hypersomnia. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
- Bogan RK, Arnulf I, Thorpy MJ, et al. Efficacy and safety of lower-sodium oxybate in adults with idiopathic hypersomnia, with and without long sleep time. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
- Dauvilliers Y, Evangelista E, Barateau L, et al. Measurement of symptoms in idiopathic hypersomnia: the Idiopathic Hypersomnia Severity Scale. Neurology. 2019;92(15):e1754-e1762.