sodium-oxybate and Sleepiness

Randomized controlled trials (RCTs) that compared the safety and efficacy of medical treatments for narcolepsy were analyzed using network meta-analysis.. The RCTs in narcolepsy were searched. Network meta-analysis compared efficacy and safety of multiple treatments, multi-arm studies, and multi-criteria treatment decisions, based on a random model that assumed heterogeneity between studies, with corrections for multi-arm studies.. Fourteen RCTs, three drug treatments, and six doses were identified: sodium oxybate (6 and 9 g/d), modafinil (between 200 and 400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Significant heterogeneity (>50%) between studies was found in 12/14 studies for almost all endpoints, but between-design consistency was present. For ESS and MWT, sodium oxybate 9 g/d, modafinil, and pitolisant up to 40 mg/d had similar efficacy. Pitolisant 40 mg/d and sodium oxybate 9 g/d in two nightly doses had similar efficacy in reducing cataplexy. A good safety profile characterized by a TEAE incidence risk ratio (IRR) <1.5 was found for all the compared treatments, except for sodium oxybate 9 g/d. Although no significant difference was found, Pitolisant 40 mg was shown with the best P scores for the benefit/risk (BR) ratio.. Modafinil (200-400 mg/d), sodium oxybate 9 g/d, and pitolisant up to 40 mg/d had similar efficacy in reducing excessive day time sleepiness. Only sodium oxybate 9 g/d and pitolisant up to 40 mg/d were shown with a comparable beneficial effect on cataplexy. Overall, Pitolisant was found with the best P score on the BR ratio.. PROSPERO 2017 CRD42017054686. Efficacy, safety, and benefit-risk comparison of alternative treatments in narcolepsy: a network multiple comparisons of treatment meta-analysis. http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017054686.

Topics: Adult; Cataplexy; Humans; Modafinil; Narcolepsy; Network Meta-Analysis; Odds Ratio; Piperidines; Risk Assessment; Sleepiness; Sodium Oxybate

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.. 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.. In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105). For the three coprimary endpoints and Epworth Sleepiness Scale, all three doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement versus placebo (all p < 0.001). For ON-SXB 9 g versus placebo, increase in mean sleep latency was 10.8 versus 4.7 min (Least squares mean difference, LSMD [95% CI], 6.13 [3.52 to 8.75]), 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76 to 11.23]), change in mean weekly number of cataplexy attacks was -11.5 versus -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.. ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.. ClinicalTrials.gov: NCT02720744, https://clinicaltrials.gov/ct2/show/NCT02720744.

Topics: Cataplexy; Double-Blind Method; Humans; Narcolepsy; Sleepiness; Sodium Oxybate; Treatment Outcome; Wakefulness

Our objective was to define responder criteria using an anchor-based approach for frequency of cataplexy attacks and excessive daytime sleepiness in patients with narcolepsy undergoing sodium oxybate treatment. We used pooled data from two randomized, placebo-controlled, double-blind, multicentre 4- and 8-week trials of sodium oxybate for narcolepsy with cataplexy and analysed using receiver operator characteristics analysis. The percentage change in frequency of weekly cataplexy attacks and the Epworth Sleepiness Scale outcomes were compared with Clinical Global Impression of Change ratings, used as the anchor to define true response. Participants (n = 336) were 39% male, 89% white, with a mean age of 41.5 (15.3) years, reporting a median of 20.5 cataplexy attacks per week and a mean Epworth Sleepiness score of 17.5 at baseline. A majority (51%) were Much Improved or Very Much Improved based on Clinical Global Impression of Change ratings, considered a true response to treatment. Area under the curve values for % reduction in cataplexy attacks (77%) and % change in sleepiness score (78%) supported response definition thresholds of 46% and 12%, respectively. Classification using either response definition agreed with the anchor for approximately 71% of participants. Cataplexy response definition was more sensitive (cataplexy = 0.77, Epworth Sleepiness Scale = 0.69), while sleepiness was more specific (cataplexy = 0.66, Epworth Sleepiness Scale = 0.75). Both responder definitions showed a dose-response relationship with sodium oxybate, demonstrating their validity using an external criterion. Weekly cataplexy attacks and Epworth Sleepiness Scale can be used to help document clinical response to narcolepsy treatment using criteria of 46% and 12% reductions, respectively.

Topics: Adjuvants, Anesthesia; Adult; Cataplexy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Sleepiness; Sodium Oxybate; Treatment Outcome; Wakefulness

Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management.. A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved.. A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.. Narcolepsia multirresistente.. Introducción. La narcolepsia de tipo 1 es una enfermedad degenerativa focal del hipotálamo que afecta selectivamente a las neuronas productoras de orexina (hipocretina). Presenta múltiples manifestaciones clínicas, tanto en vigilia como en sueño. Con frecuencia, los síntomas son tan disruptivos que ocasionan enorme sufrimiento y deterioro de la calidad de vida de los pacientes. Aunque en ocasiones es suficiente con un abordaje no farmacológico, la gran mayoría de los enfermos necesita medicación para un adecuado control clínico. Caso clínico. Varón que a los 43 años comenzó a presentar de forma aguda excesiva somnolencia diurna y episodios de cataplejía. Tras un exhaustivo estudio se le diagnosticó narcolepsia de tipo 1. A lo largo de la evolución de la enfermedad se le prescribieron antidepresivos, neuroestimulantes y oxibato sódico, en monoterapia o en combinación. La respuesta al tratamiento farmacológico fue insuficiente y se acompañó de numerosos efectos secundarios. Tras la introducción de pitolisant se objetivó una franca mejoría de los síntomas, y se consiguió reducir la dosis de los otros fármacos y de sus efectos adversos. Conclusión. Son numerosas las medidas disponibles en la actualidad para abordar los síntomas cardinales de la enfermedad, aunque siguen existiendo casos resistentes al tratamiento antinarcoléptico. Los fármacos con mecanismos de acción sobre receptores del sistema histaminérgico pueden resultar de gran utilidad en estos casos.

Topics: Adult; Antidepressive Agents; Cataplexy; Central Nervous System Stimulants; Drug Resistance, Multiple; Humans; Male; Narcolepsy; Quality of Life; Sleepiness; Sodium Oxybate

The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) measures daytime sleepiness, but had not previously been validated in children <12 years of age.. Data from a sodium oxybate (SXB) study in pediatric participants with narcolepsy with cataplexy (ClinicalTrials.gov, NCT02221869) were used in this validation study. SXB-naive participants completed an open-label titration period prior to entering a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period.. The analysis population (N = 100) had a mean (SD) age of 11.9 (2.39) years. Internal consistency as assessed by Cronbach's alpha was 0.750 (95% CI, 0.681-0.819). The intraclass correlation coefficient for the test-retest reliability assessment (n = 64 with stable or no stimulant use at study entry) was 0.755 (95% CI, 0.626-0.844). Responsiveness to change, measured as the mean within-person change in 1-week ESS-CHAD score over time in SXB-naive participants (n = 59) from baseline (before taking SXB) to end of the stable-dose period (taking the titrated amount of SXB), was -6.31 (95% CI: -7.61, -5.00; nominal P < 0.0001). For convergent construct validity, the mean (SD) scores for female (n = 40) and male (n = 60) participants were 13.98 (4.440) and 14.65 (4.050), respectively (nominal P = 0.4430). For divergent construct validity, the mean (SD) scores were 16.31 (2.978) in the group who were taking neither SXB nor stimulants at study entry (n = 32) and 13.47 (4.400) in the group taking SXB with or without stimulants at study entry (n = 68; nominal P = 0.0003).. This evidence supports the validity of the 1-week ESS-CHAD in a pediatric population with narcolepsy.

Topics: Adolescent; Cataplexy; Child; Female; Humans; Male; Narcolepsy; Reproducibility of Results; Sleepiness; Sodium Oxybate; Surveys and Questionnaires; Treatment Outcome