Dataset Information

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

ABSTRACT:

Study objectives

To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy.

Methods

These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, participants entering on modafinil (n = 231) received placebo (n = 56), SXB (n = 55), modafinil (n = 63), or SXB and modafinil (n = 57). SXB was initiated at 6 g for weeks 1-4 and increased to 9 g for weeks 5-8. TEAEs reported more frequently in SXB-treated participants than placebo and in ≥5% of any SXB treatment group during week 1 were examined as TEAEs of interest.

Results

Dizziness and nausea met criteria as TEAEs of interest in both studies; headache also met criteria as a TEAE of interest in SXB-15. Incidence of new or worsened TEAEs was highest at week 1 (SXB-15: dizziness, 7.5%; headache, 7.5%; nausea, 5.9%; SXB-22: dizziness, 5.4%; nausea, 7.1%) and decreased over time in both studies. The longest median duration was reported for dizziness: 9.0 and 17.5 days in SXB-15 and SXB-22, respectively. Dizziness caused discontinuation in 2.2% and 3.6% of participants in SXB-15 and SXB-22, respectively; nausea caused discontinuation in 2.7% and 1.8%.

Conclusions

Common early-onset TEAEs associated with SXB treatment were generally of short duration and their incidence decreased over time. These TEAEs accounted for few discontinuations overall.

Clinical trials registration

Registry: ClinicalTrials.gov; Names: Safety and Efficacy of Xyrem Oral Solution (Sodium Oxybate) Compared With Placebo in Narcoleptic Patients; Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy; URLs: https://clinicaltrials.gov/ct2/show/NCT00049803 and https://clinicaltrials.gov/ct2/show/NCT00066170; Identifiers: NCT00049803 and NCT00066170.

SUBMITTER: Husain AM

PROVIDER: S-EPMC7970612 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

Husain Aatif M AM Bujanover Shay S Ryan Robert R Scheckner Brian B Black Jed J Profant Judi J

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 20200901 9

<h4>Study objectives</h4>To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy.<h4>Methods</h4>These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, p ...[more]

PMID: 32356515

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Project description:Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient's life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.

Project description:BackgroundThe safety and efficacy of low-sodium oxybate (LXB; Xywav®) were established in a randomized, double-blind, placebo-controlled, phase 3 withdrawal study in adults with narcolepsy with cataplexy; however, the longer-term safety profile has not yet been examined. The aim of the current analysis was to assess the time of onset and duration of common treatment-emergent adverse events (TEAEs) for LXB throughout the open-label optimized treatment and titration period (OLOTTP) and the stable dose period (SDP) portions of the main study, and the subsequent 24-week open-label extension (OLE).MethodsIn a double-blind, placebo-controlled, randomized withdrawal trial of LXB, TEAEs were evaluated during the 12-week OLOTTP, the 2-week SDP, and the subsequent 24-week OLE. Eligible participants were aged 18-70 years with a diagnosis of narcolepsy with cataplexy. At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic-treatment naive; other anticataplectics were tapered and discontinued during the OLOTTP. All participants initiated LXB during week 1 of the OLOTTP, and their dose was individually titrated based on safety and efficacy. Following the main study period, participants entered the OLE after rescreening (re-entry) after discontinuing LXB treatment or directly after completing the main study (rollover). TEAEs were assessed in the safety population as of database lock. TEAE duration was defined as time from TEAE start date to end date (or end of SDP or OLE, if end date was unrecorded).ResultsThe safety population included 201 participants (SXB alone, n = 52; SXB with other anticataplectics, n = 23; other anticataplectics alone, n = 36; anticataplectic-treatment naive, n = 90). During the OLOTTP/SDP, headache was the most common LXB-emergent TEAE overall (71 events; n = 42 (21%); median (range) duration = 1 (1-147) day), followed by nausea (31 events; n = 26 (13%); median (range) duration = 9 (1-54) days) and dizziness (26 events; n = 21 (10%); median (range) duration = 7 (1-117) days). Among the 74 participants in the OLE, the most commonly reported TEAEs were headache (14 events; n = 7, 9%; peak incidence month 3 (n = 5/72); median (range) duration = 1 (1‒25) day), dizziness (8 events; n = 5, 7%; peak incidence month 1 (n = 3/74); median (range) duration = 26 (1‒181) days), and nasopharyngitis (6 events; n = 6, 8%; peak incidence month 6 (n = 2/69); median (range) duration = 9 (1‒24) days). Overall, study discontinuations attributed to TEAEs were 21/65 (32%) during the OLOTTP and SDP and 3/7 (43%) during the OLE.ConclusionsIn this long-term analysis, the safety and tolerability profile of LXB was generally consistent with the known safety profile of SXB. During the OLOTTP and SDP, most TEAEs occurred early and were generally of short duration. TEAE prevalence decreased throughout the duration of the OLE; the most common TEAEs reported during the OLE were headache, dizziness, and nasopharyngitis.Trial registrationClinicalTrials.gov identifier NCT03030599 (25 January 2017).

Project description:Study objectivesThis post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment.MethodsParticipants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups.ResultsCommon early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity.ConclusionsCommon early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606.CitationRosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med. 2022;18(1):235-244.

Dataset Information

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

Study objectives

Methods

Results

Conclusions

Clinical trials registration

Publications

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

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