The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to ...low-sodium oxybate (LXB; 92 % less sodium than SXB).
TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition.
TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %).
Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium.
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•Transition from sodium oxybate to low-sodium oxybate for narcolepsy was evaluated.•Dosing and transition characteristics were examined via questionnaire over 21 weeks.•Most participants switched for long-term health reasons due to low sodium content.•Most switched gram-for-gram, and did not require low-sodium oxybate adjustments.•Dosing was generally maintained at twice-nightly equal dosing after transition.
Registry: ClinicalTrials.gov; Name: A Patient-Centric, Prospective, Observational, Non-Interventional Switch Study of XYWAV in Narcolepsy. URL: https://clinicaltrials.gov/ct2/show/NCT04803786; Identifier: NCT04803786.
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.
The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study was conducted to provide real-world insight into the experience of people with narcolepsy switching ...from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92% less sodium than SXB).
TENOR is a patient-centric, prospective, observational, virtual-format study. Participants were adults with narcolepsy (type 1 or 2) who were transitioning from SXB to LXB treatment (±7 days from LXB initiation). Effectiveness and tolerability data were collected online from baseline (taking SXB) through 21 weeks (taking LXB) via daily and weekly diaries and questionnaires, including the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and the British Columbia Cognitive Complaints Inventory (BC-CCI).
TENOR participants (N = 85) were 73% female with a mean (SD) age of 40.3 (13.0) years. Mean (SD) ESS scores decreased numerically throughout the transition from SXB to LXB (baseline: 9.9 5.2; week 21: 7.5 4.7), with 59.5% and 75.0% of participants having scores in the normal range (≤10) at baseline and week 21, respectively. Mean (SD) FOSQ-10 scores (baseline: 14.4 3.4; week 21: 15.2 3.2) and BC-CCI scores (baseline: 6.1 4.4; week 21: 5.0 4.3) also remained stable. The most common symptoms related to tolerability reported by participants at baseline were sleep inertia, hyperhidrosis, and dizziness (45.2%, 40.5%, and 27.4%, respectively), which decreased in prevalence by week 21 (33.8%, 13.2%, and 8.8%, respectively).
Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment.
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•Transition from high-sodium to low-sodium oxybate for narcolepsy was evaluated.•Effectiveness was maintained following the transition to low-sodium oxybate.•Symptoms related to tolerability remained mostly stable.•This real-world data informs expectations about transitioning to low-sodium oxybate.
The illicit recreational drug of abuse, γ-hydroxybutyrate (GHB) is a potent central nervous
system depressant and is often encountered during forensic investigations of living and deceased
persons. ...The sodium salt of GHB is registered as a therapeutic agent (Xyrem ® ), approved in some
countries for the treatment of narcolepsy-associated cataplexy and (Alcover ® ) is an adjuvant
medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced
endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a
precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Available information
indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to
the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues,
owing to the availability of precursor drugs, γ -butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated.
After ingestion both GBL and BD are rapidly converted into GHB (t ½ ~1 min). The Cmax occurs after 20-40 min and
GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in
urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug
use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a
concentration in plasma of ~100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from
cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The
poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis.
After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to
unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from
administering benzodiazepines.
Aims
γ‐Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as a recreational substance. Nevertheless, there are limited data on the pharmacokinetics and ...pharmacokinetic‐pharmacodynamic relationships of GHB in humans. We characterized the pharmacokinetic profile and exposure‐psychotropic effect relationship of GHB in humans.
Methods
Two oral doses of GHB (25 and 35 mg kg−1) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo‐controlled, cross‐over design.
Results
Maximal concentrations of GHB were (geometric mean and 95% CI): 218 (176–270) nmol ml−1 and 453 (374–549) nmol ml−1 for the 25 and 35 mg kg−1 GHB doses, respectively. The elimination half‐lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95% CI) were 15 747 (12 854–19 290) and 40 113 (33 093–48 622) nmol∙min ml−1 for the 20 and 35 mg kg−1 GHB doses, respectively. Thus, plasma GHB exposure (AUC0‐∞) rose disproportionally (+40%) with the higher dose. γ‐Hydroxybutyrate produced mixed stimulant‐sedative effects, with a dose‐dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance).
Conclusion
Evidence was found of a nonlinear dose‐exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance.
Abstract
Study Objectives
Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and ...disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2).
Methods
Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2–3; 7.5 g, weeks 4–8; and 9 g, weeks 9–13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups.
Results
The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2.
Conclusions
Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.
Graphical Abstract
Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and ...derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4-butanediol (1,4-BD) use extracted from the UK's National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%); young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0-6500; SD 758)mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption.
Despite a better safety profile than illicit γ-hydroxybutyric acid (GHB) and other GHB analogs, sodium oxybate continues to raise serious concerns regarding clinical safety. In this study, the ...authors report the case of near-fatal intoxication involving sodium oxybate-alcohol combination in a 40-year-old woman. In addition, a review of the literature on published cases of intoxication involving this pharmaceutical form of GHB was conducted. A 40-year-old woman was admitted to the intensive care unit in a coma after voluntary ingestion of 18 g of sodium oxybate and alcohol.
The GHB plasma concentration was quantified to be 146 mg/L using liquid chromatography coupled with tandem mass spectrometry. An English literature search was performed using PubMed without any limiting period to identify all available scientific publications involving cases of sodium oxybate intoxication.
Six cases were identified. Five involved fatal intoxication cases, with GHB postmortem blood concentrations ranging from 11.5 to 3500 mg/L. One involved a nonfatal intoxication case with a GHB serum concentration of 569 mg/L 7 hours postingestion.
In the present case, the estimated elimination half-life was 154 minutes. The risk of acute poisoning seems to be high considering the pharmacokinetic properties of sodium oxybate. Physicians and toxicologists must take such properties into account.
GHB is used therapeutically and recreationally, although the precise mechanism of action responsible for its different behavioral effects is not entirely clear. The purpose of this review is to ...summarize how behavioral procedures, especially drug discrimination procedures, have been used to study the mechanism of action of GHB. More specifically, we will review several different drug discrimination procedures and discuss how they have been used to qualitatively and quantitatively study different components of the complex mechanism of action of GHB. A growing number of studies have provided evidence that the behavioral effects of GHB are mediated predominantly by GABAB receptors. However, there is also evidence that the mechanisms mediating the effects of GHB and the prototypical GABAB receptor agonist baclofen are not identical, and that other mechanisms such as GHB receptors and subtypes of GABAA and GABAB receptors might contribute to the effects of GHB. These findings are consistent with the different behavioral profile, abuse liability, and therapeutic indications of GHB and baclofen. A better understanding of the similarities and differences between GHB and baclofen, as well as the pharmacological mechanisms of action underlying the recreational and therapeutic effects of GHB, could lead to more effective medications with fewer adverse effects.
Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol ...abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the “date–rape drug”; current use in popular culture includes recreational “chemsex,” due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration–effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABA
B
receptors in the brain, with pharmacological/toxicological effects mainly due to GABA
B
agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1–4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses.
Graphical abstract
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