Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients.

STUDY OBJECTIVES: Evaluate long-term efficacy and safety of sodium oxybate (SXB) in children and adolescents (aged 7-16 years) with narcolepsy with cataplexy. METHODS: A double-blind randomized withdrawal study was conducted. Prior to randomization, SXB-naive participants were titrated to an efficacious and tolerable dose of SXB; participants taking SXB entered on their established dose. Following a 2-week stable-dose period and 2-week, double-blind, randomized withdrawal period, participants entered an open-label period (OLP; ≤ 47 weeks). Efficacy measures during the OLP included number of weekly cataplexy attacks, cataplexy-free days, and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Safety outcomes included treatment-emergent adverse events; assessments of depression, anxiety, and suicidality; and polysomnography. RESULTS: Of 106 enrolled participants, 95 entered and 85 completed the OLP. In SXB-naive participants and participants previously taking SXB, efficacy of SXB established prior to the double-blind, randomized withdrawal period was maintained throughout the OLP for number of weekly cataplexy attacks (median [quartile 1, quartile 3] change from the stable-dose period to end of the OLP: 0.0 [-2.5, 4.9] and 0.0 [-3.4, 2.6], respectively) and ESS-CHAD scores (0.0 [-3.0, 2.5] and 1.0 [-3.0, 3.0], respectively). The median (quartile 1, quartile 3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in OLP week 1 and 3.8 (0.5, 5.5) in week 48. Treatment-emergent adverse events (≥ 5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, upper respiratory tract infection, and dizziness. CONCLUSIONS: SXB demonstrated long-term maintenance of efficacy in pediatric narcolepsy with cataplexy, with a safety profile consistent with that observed in adults. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem with an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy; URL: https://clinicaltrials.gov/ct2/show/NCT02221869; Identifier: NCT02221869. CITATION: Lecendreux M, Plazzi G, Dauvilliers Y, et al. Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients. J Clin Sleep Med. 2022;18(9):2217-2227.

Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation.

BACKGROUND: Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy. METHODS: This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7-16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with ClinicalTrials.gov, number NCT02221869. FINDINGS: Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [-1·0, 2·5]; p<0·0001). Commonly reported (>5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths. INTERPRETATION: These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients. FUNDING: Jazz Pharmaceuticals.

Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy.

OBJECTIVE: To assess the effects of three narcolepsy treatment modalities on sleep stage shifts associated with disrupted nighttime sleep (DNS) using data from a clinical trial. METHODS: Polysomnograms were reviewed from 155 patients (who had these data available at baseline and 8 weeks) of the 278 patients who were randomized to placebo, 9-g sodium oxybate (SXB)/nightly, 200-600 mg/d modafinil, or SXB + modafinil. Major outcomes of these post hoc analyses, analyzed using analysis of covariance, were change from baseline in number of shifts from Stages N2/3/rapid eye movement (REM) to Stage N1/Wake, and from Stage N1/Wake to REM. Sleep quality was evaluated using the sleep-quality question from the Pittsburgh Sleep Quality Index. RESULTS: SXB alone or in combination with modafinil significantly decreased the number of shifts from Stage N2/3/REM to Stage N1/Wake (p < 0.01); least-squares mean change in number of shifts from baseline was -0.6, -16.5, 1.8, and -13.7 in the placebo, SXB, modafinil and SXB + modafinil groups, respectively. A similar pattern was observed for changes in shifts from REM to Stage N1/Wake and from Stage N1/Wake to REM. Relative to placebo, sleep quality significantly improved with SXB and SXB + modafinil (p ≤ 0.05) but not with modafinil alone. CONCLUSION: These results show that SXB with and without modafinil significantly consolidated sleep and improved patient-reported sleep quality relative to placebo. In contrast, no such effects were observed with modafinil alone, suggesting a specific effect of SXB on DNS in addition to its effect on daytime sleepiness. CLINICALTRIALS. GOV IDENTIFIER: NCT00066170.

Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy.

This post hoc analysis evaluated the dose-related effects of sodium oxybate on sleep continuity and nocturnal sleep quality in patients with narcolepsy-cataplexy. Polysomnography data, including shifts to Stage N1/Wake, were from a randomized, placebo-controlled trial of sodium oxybate. Patients were ≥16 years old with a diagnosis of narcolepsy including symptoms of cataplexy and excessive daytime sleepiness. Treatment was for 8 weeks with placebo or sodium oxybate 4.5, 6 or 9 g administered as two equally divided nightly doses. Relative to baseline, significant dose-dependent reductions in the number of shifts per hour from Stages N2/3/rapid eye movement and Stages N2/3 to Stage N1/Wake were observed at week 8 with sodium oxybate (P < 0.05); sodium oxybate 6- and 9-g doses also resulted in similar reductions in shifts per hour of rapid eye movement to Stage N1/Wake (both P < 0.05). Across all shift categories, the shift reductions with sodium oxybate 9 g were significantly greater than those observed with placebo (P < 0.05). Improvements from baseline in reported sleep quality were significantly greater with sodium oxybate 4.5 and 9 g at week 8 (P < 0.05). Correlations between change from baseline in number of shifts per hour to Stage N1/Wake and cataplexy frequency, patient-reported nocturnal sleep quality, and excessive daytime sleepiness assessed using the Epworth Sleepiness Scale were numerically highest for the sodium oxybate 9-g dose across all sleep stage shift categories. In these patients with narcolepsy, sodium oxybate showed improvements in the sleep continuity and nocturnal sleep quality that are characteristic of disrupted nighttime sleep (ClinicalTrials.gov identifier NCT00049803).

Increased mortality in narcolepsy.

OBJECTIVE: To evaluate the mortality rate in patients with narcolepsy. DESIGN: Data were derived from a large database representative of the US population, which contains anonymized patient-linked longitudinal claims for 173 million individuals. SETTING: Symphony Health Solutions (SHS) Source Lx, an anonymized longitudinal patient dataset. PATIENTS/PARTICIPANTS: All records of patients registered in the SHS database between 2008 and 2010. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Identification of patients with narcolepsy was based on ≥ 1 medical claim with the diagnosis of narcolepsy (ICD-9 347.xx) from 2002 to 2012. Dates of death were acquired from the Social Security Administration via a third party; the third party information was encrypted in the same manner as the claims data such that anonymity is ensured prior to receipt by SHS. Annual all-cause mortality rates for 2008, 2009, and 2010 were calculated retrospectively for patients with narcolepsy and patients without narcolepsy in the database, and standardized mortality ratios (SMR) were calculated. Mortality rates were also compared with the general US population (Centers for Disease Control data). SMRs of the narcolepsy population were consistent over the 3-year period and showed an approximate 1.5-fold excess mortality relative to those without narcolepsy. The narcolepsy population had consistently higher mortality rates relative to those without narcolepsy across all age groups, stratified by age decile, from 25-34 years to 75+ years of age. The SMR for females with narcolepsy was lower than for males with narcolepsy. CONCLUSIONS: Narcolepsy was associated with approximately 1.5-fold excess mortality relative to those without narcolepsy. While the cause of this increased mortality is unknown, these findings warrant further investigation.

Long-term tolerability and maintenance of therapeutic response to sodium oxybate in an open-label extension study in patients with fibromyalgia.

INTRODUCTION: The long-term safety and therapeutic response of sodium oxybate (SXB) in fibromyalgia syndrome (FM) patients were assessed for a combined period of up to 1 year in a prospective, multicenter, open-label, extension study in patients completing 1 of 2 phase 3 randomized, double-blind, controlled, 14-week trials that examined the efficacy and safety of SXB 4.5 g, SXB 6 g, and placebo for treatment of FM. METHODS: This extension study comprised an additional 38 weeks of treatment and was carried out at 130 clinical sites in 7 countries. Initial entry criteria for the previous 2 double-blind clinical trials required that patients aged ≥ 18 years met the American College of Rheumatology 1990 criteria for FM, had a body mass index (BMI) < 40 kg/m2, and had a score ≥ 50 on a 100-mm pain visual analog scale (VAS) at baseline. All patients began treatment in the extension study with SXB 4.5 g/night (administered in 2 equally divided doses) for at least 1 week, followed by possible serial 1.5 g/night dose increases to 9 g/night (maximum) or reductions to 4.5 g/night (minimum). RESULTS: Of the 560 FM patients enrolled in this extension study, 319 (57.0%) completed the study. The main reason for early discontinuation was adverse events (AEs; 23.0% of patients). Patients were primarily middle-aged (mean 46.9 ± 10.8 years), female (91.1%), white (91.4%), with a mean duration of FM symptoms of 9.9 ± 8.7 years. Serious AEs were experienced by 3.6% of patients. The most frequently reported AEs (incidence ≥ 5% at any dose or overall) were nausea, headache, dizziness, nasopharyngitis, vomiting, sinusitis, diarrhea, anxiety, insomnia, influenza, somnolence, upper respiratory tract infection, muscle spasms, urinary tract infection, and gastroenteritis viral. Maintenance of SXB therapeutic response was demonstrated with continued improvement from controlled-study baseline in pain VAS, Fibromyalgia Impact Questionnaire (FIQ) total scores, and other measures. Responder analyses showed that 68.8% of patients achieved ≥ 30% reduction in pain VAS and 69.7% achieved ≥ 30% reduction in FIQ total score at study endpoint. CONCLUSIONS: The long-term safety profile of SXB in FM patients was similar to that in the previously reported controlled clinical trials. Improvement in pain and other FM clinical domains was maintained during long-term use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00423605.

Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study.

This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a ≥30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6 g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of "much" or "very much" better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: To determine the effects of sodium oxybate (SXB) on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome (FM). METHODS: Of 304 patients with FM (American College of Rheumatology tender point criteria) in the screened study population, 209 underwent polysomnography, 195 were randomized, and 151 completed this 8-week, double-blind, placebo-controlled study of SXB 4.5 g and 6 g/night. We evaluated changes in objective sleep measures and subjective symptoms, including daytime sleepiness [Epworth Sleepiness Scale (ESS)], fatigue visual analog scale (FVAS), sleep [Jenkins Scale for Sleep (JSS)], and daytime functioning [Functional Outcome of Sleep Questionnaire (FOSQ), SF-36 Vitality domain, and Fibromyalgia Impact Questionnaire (FIQ) general and morning tiredness]. RESULTS: Pretreatment screening revealed an elevated incidence of maximum alpha EEG-intrusion > 24 min/hour of sleep (66%), periodic limb movements of sleep (20.1% ≥ 5/hour), and moderate to severe obstructive sleep apnea disorder (15.3% apnea-hypopnea index ≥ 15/hour). Compared with placebo, both doses of SXB achieved statistically significant improvements in ESS, morning FVAS, JSS, FOSQ, SF-36 Vitality, and FIQ general and morning tiredness; both doses also demonstrated decreased rapid eye movement (REM) sleep (all p ≤ 0.040). SXB 6 g/night improved afternoon, evening and overall FVAS, reduced wakefulness after sleep onset, and increased Stage 2, slow-wave, and total non-REM sleep (all p ≤ 0.032) versus placebo. Moderate correlations (≥ 0.40) were noted between changes in subjective sleep and pain measures. Adverse events occurring significantly more frequently with SXB than placebo were nausea, pain in extremity, nervous system disorders, dizziness, restlessness, and renal/urinary disorders (including urinary incontinence). CONCLUSION: This large cohort of patients with FM demonstrated that SXB treatment improved EEG sleep physiology and sleep-related FM symptoms.