Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy

Richard K Bogan, Michael J Thorpy, Yves Dauvilliers, Markku Partinen, Rafael Del Rio Villegas, Nancy Foldvary-Schaefer, Roman Skowronski, Lihua Tang, Franck Skobieranda, Karel Šonka, Richard K Bogan, Michael J Thorpy, Yves Dauvilliers, Markku Partinen, Rafael Del Rio Villegas, Nancy Foldvary-Schaefer, Roman Skowronski, Lihua Tang, Franck Skobieranda, Karel Šonka

Abstract

Study objectives: Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB).

Methods: Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment.

Results: Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%).

Conclusions: Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB.

Clinical trial registration: NCT03030599.

Keywords: JZP-258; cataplexy; excessive daytime sleepiness; narcolepsy; sodium oxybate.

© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society.

Figures

Figure 1.
Figure 1.
Study design. DBRWP, double-blind randomized withdrawal period; LXB, lower-sodium oxybate; OL, open-label; OLOTTP, open-label optimized treatment and titration period; SDP, stable-dose period; SXB, sodium oxybate.
Figure 2.
Figure 2.
Participant disposition. DBRWP, double-blind randomized withdrawal period; LXB, lower-sodium oxybate; OLOTTP, open-label optimized treatment and titration period; SDP, stable-dose period; SXB, sodium oxybate; TEAE, treatment-emergent adverse event.
Figure 3.
Figure 3.
Change in weekly number of cataplexy attacks from the stable-dose period to the double-blind randomized withdrawal period (efficacy population). The bottom and top edges of the box indicate the first and third quartiles, the line inside the box is the median, and the marker inside the box is the mean. Any points that are a distance of more than 1.5 times the interquartile range from the box are considered outliers and are represented by circles; the whiskers extending from the box indicate the minimum and maximum after removing those outliers. LXB, lower-sodium oxybate; Q1, first quartile; Q3, third quartile. aRank-based analysis of covariance.
Figure 4.
Figure 4.
Change in the ESS score from the end of the stable-dose period to the end of the double-blind randomized withdrawal period (efficacy population). The bottom and top edges of the box indicate the first and third quartiles, the line inside the box is the median, and the marker inside the box is the mean. Any points that are a distance of more than 1.5 times the interquartile range from the box are considered outliers and are represented by circles; the whiskers extending from the box indicate the minimum and maximum after removing those outliers. ESS, Epworth Sleepiness Scale; LXB, lower-sodium oxybate; Q1, first quartile; Q3, third quartile. aRank-based analysis of covariance.

References

    1. Ohayon MM. Epidemiology of narcolepsy. In: Bassetti C, Mignot E, Billard M, eds. Narcolepsy and Hypersomnia. Milton Park, UK: Taylor and Francis; 2007:125–132.
    1. Ruoff CM, et al. . High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J Clin Psychiatry. 2017;78(2):171–176.
    1. Black J, et al. . Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13–18.
    1. American Academy of Sleep Medicine. Narcolepsy type 1. The International Classification of Sleep Disorders. 3rd ed. 2014. Available at: . Accessed November 12, 2019.
    1. Roth T, et al. . Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med. 2013;9(9):955–965.
    1. Xyrem® (Sodium Oxybate) Oral Solution Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals; 2018.
    1. Xyrem Summary of Product Characteristics. Berkshire: UCB Pharma; 2019.
    1. Xyrem Product Monograph Including Patient Medication Information. Dublin: Jazz Pharmaceuticals Ireland Limited; 2018.
    1. Morgenthaler TI, et al. . Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–1711.
    1. Billiard M, et al. . EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13(10):1035–1048.
    1. Barateau L, et al. . Treatment options for narcolepsy. CNS Drugs. 2016;30(5):369–379.
    1. Lopez R, et al. . French consensus. management of patients with hypersomnia: which strategy? Rev Neurol (Paris). 2017;173(1–2):8–18.
    1. U.S. Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25(1):42–49.
    1. U.S. Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5(2):119–123.
    1. Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med. 2005;6(5):415–421.
    1. Black J, et al. . Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006;29(7):939–946.
    1. Plazzi G, et al. . Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018;2(7):483–494.
    1. Institute of Medicine. Sodium Intake in Populations: Assessment of Evidence. Washington, DC: The National Academies Press; 2013.
    1. Gardener H, et al. . Dietary sodium and risk of stroke in the northern Manhattan study. Stroke. 2012;43(5):1200–1205.
    1. George J, et al. . Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested case-control study. BMJ. 2013;347:f6954.
    1. American Heart Association. Why should I limit sodium?2017. Available at: . Accessed July 18, 2019.
    1. National Academies of Sciences, Engineering, and Medicine. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press; 2019.
    1. Centers for Disease Control and Prevention. Get the facts: sodium and the dietary guidelines. 2017. Available at: . Accessed October 4, 2019.
    1. European Commission. Survey on members states’ implementation of the EU salt reduction framework. 2012. Available at: . Accessed November 12, 2019.
    1. Perrin G, et al. . Cardiovascular risk associated with high sodium-containing drugs: a systematic review. PLoS One. 2017;12(7):e0180634.
    1. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14(6):488–492.
    1. Cohen A, et al. . Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14–18.
    1. Dauvilliers Y, et al. . Non-dipping blood pressure profile in narcolepsy with cataplexy. PLoS One. 2012;7(6):e38977.
    1. McAlpine CS, et al. . Sleep modulates haematopoiesis and protects against atherosclerosis. Nature. 2019;566(7744):383–387.
    1. Medic G, et al. . Short- and long-term health consequences of sleep disruption. Nat Sci Sleep. 2017;9:151–161.
    1. Poli F, et al. . Body mass index-independent metabolic alterations in narcolepsy with cataplexy. Sleep. 2009;32(11):1491–1497.
    1. Grimaldi D, et al. . Abnormal sleep-cardiovascular system interaction in narcolepsy with cataplexy: effects of hypocretin deficiency in humans. Sleep. 2012;35(4):519–528.
    1. Domínguez F, et al. . Association of sleep duration and quality with subclinical atherosclerosis. J Am Coll Cardiol. 2019;73(2):134–144.
    1. Thurston RC, et al. . Sleep characteristics and carotid atherosclerosis among midlife women. Sleep. 2017;40(2). doi: 10.1093/sleep/zsw052.
    1. Honda Y, et al. . Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep. 1986;9(1 Pt 2):254–259.
    1. Ben-Dov IZ, et al. . Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension. 2007;49(6):1235–1241.
    1. XywavTM (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals; 2020.
    1. Chen C, et al. . Pharmacokinetics, relative bioavailability, and food effect of JZP-258 and sodium oxybate: results of two phase 1, open-label, randomised crossover studies in healthy volunteers [poster]. Presented at: Biennial World Sleep Congress; September 20–25, 2019; Vancouver, Canada.
    1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
    1. American Psychiatric Association. Narcolepsy. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:372–378.
    1. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–545.
    1. Hays RD, et al. . Construct validity of MOS health measures. In: Stewart AL, Ware JE, eds. Measuring Functioning and Well-being: The Medical Outcomes Study Approach. Durham, NC: Duke University Press; 1992:325–342.
    1. Ware JE Jr, et al. . The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483.
    1. van Reenen M, et al. . EQ-5D-5L User Guide. Rotterdam: EuroQol Research Foundation; 2015.
    1. Posner K, et al. . The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277.
    1. Kroenke K, et al. . The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–613.
    1. Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med. 2005;1(4):391–397.
    1. Ristanovic RK, et al. . Exacerbation of cataplexy following gradual withdrawal of antidepressants: manifestation of probable protracted rebound cataplexy. Sleep Med. 2009;10(4):416–421.
    1. Daniels E, et al. . Health-related quality of life in narcolepsy. J Sleep Res. 2001;10(1):75–81.
    1. Bogan R, et al. . Evaluation of quality of life in patients with narcolepsy treated with sodium oxybate: use of the 36-item short-form health survey in a clinical trial. Neurol Ther. 2016;5(2):203–213.
    1. Jenkinson C, et al. . Comparison of three measures of quality of life outcome in the evaluation of continuous positive airways pressure therapy for sleep apnoea. J Sleep Res. 1997;6(3):199–204.
    1. Fava GA, et al. . Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87(4):195–203.
    1. Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4:45.
    1. American Psychiatric Association. Medication-Induced Movement Disorders and Other Adverse Effects of Medication. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
    1. US Food and Drug Administration. Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products. 2019. Available at: . Accessed March 27, 2020.
    1. Black J, et al. . The nightly administration of sodium oxybate results in significant reduction in the nocturnal sleep disruption of patients with narcolepsy. Sleep Med. 2009;10(8):829–835.
    1. Black J, et al. . The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med. 2010;6(6):596–602.
    1. Dauvilliers Y, et al. . Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy. Sleep Med. 2017;40:53–57.
    1. Roth T, et al. . Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res. 2017;26(4):407–414.
    1. Filardi M, et al. .. In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: an actigraphic study. Sleep. 2018;41(6). doi: 10.1093/sleep/zxy050.
    1. Thorpy MJ, et al. . The Nexus narcolepsy registry: assessment of sodium oxybate (SXB) on functioning, productivity, and health-related quality of life in participants with narcolepsy [abstract]. Neurology. 2018;90(15 Suppl):P1.105.
    1. Whelton PK, et al. . 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):e13–e115.
    1. Bibbins-Domingo K, et al. . Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med. 2010;362(7):590–599.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner