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.
Citation:
Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. 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. J Clin Sleep Med. 2020;16(9):1469–1474.
Keywords: safety, dizziness, nausea, sleepiness
BRIEF SUMMARY
Current Knowledge/Study Rationale: The incidence of treatment-emergent adverse events associated with sodium oxybate has been reported, but the time course and duration of common early-onset treatment-emergent adverse events have not been examined previously.
Study Impact: These analyses inform clinician expectations regarding the type, time course, and duration of common early-onset treatment-emergent adverse events associated with sodium oxybate. The findings also demonstrate the importance of individualized, gradual titration of sodium oxybate dose and regimen to optimize efficacy and tolerability in sodium oxybate–treated patients.
INTRODUCTION
Sodium oxybate (SXB; Xyrem; Jazz Pharmaceuticals, Inc, Palo Alto, CA) is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy.1 The efficacy and safety of SXB were demonstrated in 4 clinical trials in adult participants with narcolepsy and 1 clinical trial in pediatric participants with narcolepsy.2–5
Adverse events (AEs) associated with SXB treatment are described in the prescribing information, based on an analysis of pooled data from 3 of the 4 studies in the adult clinical trial program.1 The treatment-emergent AEs (TEAEs) that were most common (defined in the prescribing information as those with an incidence of ≥5% and twice the rate seen with placebo) included nausea, dizziness, vomiting, somnolence, and enuresis. A total of 10.3% of participants treated with SXB discontinued due to AEs, compared with 2.8% of participants receiving placebo. The most common AE leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.
The 3 clinical trials included in the pooled analysis involved different study designs, and the starting doses and titration schedules in 2 of the 3 trials differed from those specified in the prescribing information.1 The recommended initiation dose for adult patients is a total nightly dose of 4.5 g per night, divided into 2 doses1; the adult clinical trial program included studies that employed initiation doses of 3, 4.5, 6, and 9 g per night.2,4,5 With respect to titration, the recommended titration schedule in adult patients allows for dose increases of 1.5 g per week1; the adult clinical trial program included studies with titration schedules involving dose increases of 1.5 and 3 g, as well as a study involving assignment to dose, during which total nightly doses up to 9 g per night were administered without titration.2,4,5 Hence, the reported incidences from AE data pooled across studies may obscure the importance of individualized, gradual titration of dose and regimen to optimize efficacy and tolerability. Additionally, there were differences across studies in the use of wake-promoting agents and stimulants.2,4,5
The aim of the analyses reported here was to characterize the time course and duration of common, early-onset TEAEs associated with the initiation and titration of SXB. Data from 2 of the 4 studies in the adult clinical trial program were included in these analyses. The other 2 studies were excluded because one assigned participants to total nightly doses without titration2 and the second examined the impact of randomized withdrawal after long-term SXB treatment.3 The information herein provides clinicians with a more complete understanding of how AEs may evolve during treatment.6 Increased understanding of TEAEs may enhance clinical decision making, improve management of TEAEs, and enable clinicians to set appropriate expectations in order to optimize individualized treatment.
METHODS
These post hoc analyses included data from two 8-week, randomized, placebo-controlled, parallel-group, phase 3 clinical trials: SXB-15 and SXB-22. Both trials evaluated the efficacy and safety of SXB in the treatment of excessive daytime sleepiness in adults with narcolepsy.4 SXB-22 also characterized the efficacy and safety of SXB in combination with modafinil.5 In one of the trials (SXB-22), SXB was initiated at a total nightly dose of 6 g. Descriptions of study methods and results for both trials were published previously4,5 and are briefly summarized below. Both studies were approved by institutional review boards or ethics committees at each institution and performed in accordance with the Declaration of Helsinki. All participants provided written informed consent.
Participants
In SXB-15, eligible participants were at least 16 years of age with a diagnosis of narcolepsy with cataplexy for at least 3 months. In SXB-22, eligible participants were at least 18 years of age with a diagnosis of narcolepsy. In SXB-22, inclusion criteria also required having been on modafinil or stimulant medication for the treatment of excessive daytime sleepiness for at least 3 months and taking stable doses of modafinil at 200–600 mg/d for at least 1 month immediately preceding the trial or at least 6 weeks at any time prior to the trial. Cataplexy was not an enrollment criterion in SXB-22.
Key exclusion criteria for both studies included use of SXB or any investigational therapy within 30 days prior to the trial, clinically significant sleep apnea or any other cause of excessive daytime sleepiness, and use of sedative or hypnotic drugs.
Study design: SXB-15
During the double-blind treatment period, participants were randomized to SXB 4.5, 6, or 9 g per night, or placebo. Four weeks of dose titration was followed by 4 weeks of stable dosing. All participants randomized to SXB initiated treatment at a dose of 4.5 g per night. In participants randomized to SXB 6 or 9 g, the total nightly dose of SXB was increased by 1.5 g every week until the assigned dose was reached. During the stable dosing phase, participants remained on their assigned SXB dose or placebo for the remaining 4 weeks of the study. Participants taking concomitant stimulant medication at study entry were required to remain on the same dose throughout the trial.
Study design: SXB-22
All participants entered the study taking a stable dose of modafinil. During the double-blind treatment period, participants were randomized to treatment with SXB alone (SXB group), modafinil alone (modafinil group), SXB + modafinil (SXB/modafinil group), or placebo (placebo group). Participants randomized to the modafinil and SXB/modafinil groups continued to receive their customary doses of modafinil, whereas participants randomized to the SXB and placebo groups were withdrawn from modafinil. Participants randomized to the SXB and SXB/modafinil groups initiated SXB treatment at a total nightly dose of 6 g per night for 4 weeks. At week 5, the total nightly dose of SXB was increased by 3 g, such that participants received 9 g per night for the remaining 4 weeks of the study. No additional stimulants were allowed during the trial.
In both studies, the total nightly dose of SXB was divided into 2 equal doses, with the first dose taken at bedtime and the second dose 2.5 to 4 hours later.
Safety assessment
Investigators reported all AEs that occurred up to 10 days following the last dose of trial medication, regardless of association with trial medication. For each event, signs or symptoms, date of onset and date of resolution (duration), severity, relationship to treatment or other therapy, action taken, and outcome were collected. AEs reported after the start of double-blind treatment were considered TEAEs.
TEAEs reported in 5% or more of any SXB treatment group during week 1 and more frequently in SXB-treated participants than placebo were examined as TEAEs of interest. AEs that met these criteria were assessed for time course and duration. Incidences of new TEAEs and TEAEs that increased in severity over time (worsened TEAEs) were summarized by week. Duration was determined by calculating the total number of days, continuous or recurrent, that a participant experienced a TEAE.
Statistical analyses
AEs were classified using the Medical Dictionary for Regulatory Activities, version 6.0. When the date of AE onset could not be obtained from the participant record, it was assumed that the event occurred on or after the first dose. If the AE was resolved but the date of resolution was unknown, it was assumed that the event resolved after the last visit.
Due to differences in study designs, data from SXB-15 and SXB-22 were analyzed independently. Analyses were based on the all-treated populations in both studies, defined as participants who received at least 1 dose of double-blind medication. Data were presented for a placebo group and a combined SXB group, consisting of all participants treated with SXB (ie, all SXB dose groups were combined in SXB-15, and all participants treated with SXB, with and without modafinil, were combined in SXB-22). Demographic characteristics and incidence of new or worsened TEAEs of interest, as well as duration of TEAEs of interest, were summarized descriptively.
RESULTS
Participant disposition
A total of 285 participants were randomized in SXB-15. Of the 246 included in the all-treated population, 60 were randomized to placebo and 186 were randomized to SXB 4.5 g (n = 68), 6 g (n = 63), and 9 g (n = 55). A total of 78% of study participants remained on stable doses of stimulant medication. Baseline demographics were similar between participants who were randomized to placebo and those randomized to SXB (Table 1).
Table 1.
Baseline demographics by treatment group.
| Variable | SXB-15 | SXB-22 | ||
|---|---|---|---|---|
| Placebo (n = 60) | All SXB (n = 186) | Placebo (n = 56) | All SXB (n = 112) | |
| Sex, n (%) | ||||
| Male | 17 (28.3) | 66 (35.5) | 24 (42.9) | 56 (50.0) |
| Female | 43 (71.7) | 120 (64.5) | 32 (57.1) | 56 (50.0) |
| Mean (SD) age, years | 40.5 (15.6) | 40.6 (15.3) | 40.9 (13.3) | 37.7 (15.2) |
| Race, n (%) | ||||
| White | 55 (91.7) | 158 (84.9) | 44 (78.6) | 101 (90.2) |
| Black | 3 (5.0) | 22 (11.8) | 11 (19.6) | 7 (6.3) |
| Other | 2 (3.3) | 6 (3.2) | 1 (1.8) | 4 (3.6) |
The “treatment group” indicates the all-treated population. SD = standard deviation; SXB = sodium oxybate.
A total of 231 participants were randomized in SXB-22, all of whom received at least 1 dose of double-blind trial medication (placebo, n = 56; SXB, n = 55; modafinil, n = 63; SXB/modafinil, n = 57). Baseline demographics were generally similar between participants randomized to placebo and those randomized to SXB (Table 1).
Overall safety of SXB vs placebo
After initiating double-blind treatment, 69.5% of participants in SXB-15 experienced any TEAE and 65.4% of participants in SXB-22 experienced any TEAE. TEAEs that occurred in 5% or more of SXB-treated participants at any point during the double-blind treatment period and that were reported numerically more frequently in participants treated with SXB than placebo included headache, dizziness, nausea, enuresis, diarrhea, and vomiting (SXB-15) and dizziness, nausea, and vomiting (SXB-22) (Table 2).
Table 2.
TEAEs reported in ≥5% of participants receiving SXB in either study.
| TEAEs | SXB-15, n (%) | SXB-22, n (%) | ||
|---|---|---|---|---|
| Placebo (n = 60) | All SXB (n = 186) | Placebo (n = 56) | All SXB (n = 112) | |
| Headache | 7 (11.7) | 35 (18.8) | 12 (21.4) | 16 (14.3) |
| Dizziness | 1 (1.7) | 31 (16.7) | 3 (5.4) | 16 (14.3) |
| Nausea | 2 (3.3) | 34 (18.3) | 1 (1.8) | 24 (21.4) |
| Enuresis | 1 (1.7) | 16 (8.6) | 0 | 3 (2.7) |
| Nasopharyngitis | 6 (10.0) | 13 (7.0) | 4 (7.1) | 7 (6.3) |
| Diarrhea | 1 (1.7) | 10 (5.4) | 0 | 5 (4.5) |
| Vomiting | 1 (1.7) | 10 (5.4) | 0 | 12 (10.7) |
| Somnolence | 0 | 8 (4.3) | 4 (7.1) | 7 (6.3) |
Adverse events experienced after the start of the double-blind treatment in the all-treated population. SXB = sodium oxybate; TEAE = treatment-emergent adverse event.
Incidence of TEAEs over time
In SXB-15, the incidence of new or worsened TEAEs of interest among participants receiving SXB was highest at week 1, with 14 (7.5%) participants reporting dizziness, 14 (7.5%) reporting headache, and 11 (5.9%) reporting nausea (Figure 1). The incidence of these TEAEs decreased as early as week 2 (2.7%, 4.3%, and 3.8% for dizziness, headache, and nausea, respectively), with continued reductions to week 8 (0.0%, 1.1%, and 0.0%, respectively). In SXB-22, 6 (5.4%) participants reported new or worsened dizziness and 8 (7.1%) reported new or worsened nausea at week 1 (Figure 1). The incidence of these TEAEs decreased over weeks 2 (0.9% and 4.5%, respectively), 3 (1.8% and 0%), and 4 (2.7% and 2.7%). Following the scheduled dose increase of 3 g per night at week 5, the incidence of new or worsened TEAEs increased for participants treated with SXB. Following week 5, the incidence of these TEAEs again decreased over the remainder of the study, with 0.9% reporting dizziness and 0.0% reporting nausea at week 8.
Figure 1. Incidence of new or worsened TEAEs of interest.
Horizontal bars indicate SXB titration steps for each of 3 SXB dose groups in SXB-15 (A) and all participants assigned to SXB in SXB-22 (B). TEAEs that occurred more frequently in participants treated with SXB than placebo and at an incidence ≥5% in any SXB treatment group during week 1 are shown for the all-treated populations. The double-blind treatment period in SXB-15 is up to week 8; week 9 reflects post–double-blind TEAE collection. SXB = sodium oxybate; TEAE = treatment-emergent adverse event.
Duration of TEAEs
In both trials, median duration was longest for dizziness (median duration of 9.0 and 17.5 days in SXB-15 and SXB-22, respectively; Table 3). Nausea abated more quickly (median duration of 4.5 and 3.0 days in SXB-15 and SXB-22, respectively), as did headache (median of 2.0 days in SXB-15; not a common TEAE in week 1 in SXB-22), despite neither study allowing downward titration of doses.
Table 3.
Duration of TEAEs of interest among participants taking SXB.
| TEAE | SXB-15 | SXB-22 | ||
|---|---|---|---|---|
| With TEAE, n | Median (Range) Duration, Days | With TEAE, n | Median (Range) Duration, Days | |
| Dizziness | 36 | 9.0 (1.0–69.0) | 20 | 17.5 (1.0–53.0) |
| Nausea | 38 | 4.5 (1.0–57.0) | 29 | 3.0 (1.0–60.0) |
| Headache | 55 | 2.0 (1.0–58.0) | — | — |
TEAEs that occurred more frequently in participants treated with SXB than placebo and at an incidence ≥5% in any SXB treatment group during week 1 are shown for the all treated population. Data are not shown for headache in SXB-22 because this TEAE did not meet these criteria. SXB = sodium oxybate; TEAE = treatment-emergent adverse event.
Discontinuations due to TEAEs
In SXB-15, a total of 40 participants (SXB, 19.4%; placebo, 6.7%) discontinued study participation after starting double-blind treatment; of these, 21 participants (SXB, 10.8%; placebo, 1.7%) discontinued due to TEAEs. In SXB-22, a total of 30 participants (SXB, 17.0%; placebo, 12.5%) discontinued study participation after starting double-blind treatment; of these, 13 participants (SXB, 8.9%; placebo, 1.8%) discontinued due to TEAEs. In SXB-15, dizziness and nausea were reported as reasons for discontinuation in 4 (2.2%) and 5 (2.7%) SXB-treated participants, respectively. Headache was not reported as a reason for discontinuation. In SXB-22, dizziness and nausea were reported as reasons for discontinuation in 4 (3.6%) and 2 (1.8%) SXB-treated participants, respectively. Other reasons for discontinuation included loss to follow-up, noncompliance with study medication, and protocol deviation.
DISCUSSION
In SXB-15, incidence of new or worsened TEAEs of dizziness, nausea, and headache was highest during the first week of SXB treatment. Incidence of new-onset or worsening of these TEAEs diminished over time, even in the context of weekly dose increases of 1.5 g per night during SXB titration. In SXB-22, incidence of new-onset or worsening TEAEs diminished over time during the first 4 weeks of SXB treatment at a total nightly dose of 6 g per night. At week 5, the 3-g increase in total nightly dose to 9 g per night was accompanied by a marked increase in new or worsened nausea and dizziness. Incidence of new or worsened TEAEs again diminished during subsequent weeks of treatment at 9 g per night. These data support the recommended gradual titration regimen involving dose increases of up to 1.5 g per night at no more often than weekly intervals, as reflected in the prescribing information.1 Dizziness persisted longer in these clinical trials (9.0–17.5 days) than did nausea and headache.
Data on TEAEs from other comparable studies are limited to 2 trials with γ-hydroxybutyrate.7,8 Both studies were 4-week, crossover, randomized, placebo-controlled trials in participants with narcolepsy with cataplexy, who received a fixed amount of γ-hydroxybutyrate that was based on weight and split evenly into 2 doses per night. In the first study (n = 20), at a total dose of 50 mg/kg per night, the following AEs were reported during treatment with γ-hydroxybutyrate: upset stomach (n = 3); upset stomach with vomiting during the first week of treatment (n = 1); sluggishness and stiffness upon morning awakening (n = 2); dizziness after the second dose of the night (n = 1); urinary urgency (n = 1); cataplexy during physical exertion, which had never previously occurred (n = 1); general weakness and fatigue (n = 1); and 1 episode of dizziness during the day (n = 1).7 In the second study (n = 24), at a total dose of 60 mg/kg per night, the following AEs were reported in participants during treatment with γ-hydroxybutyrate: protracted sleep paralysis in combination with a hypnagogic hallucination during the first week of treatment (n = 1) and weight loss during the first 2 weeks of treatment (n = 1).8 The smaller sample sizes and shorter duration of the previous studies constrain meaningful comparisons of safety relative to our analyses. A third study in participants with narcolepsy who received SXB or placebo was not comparable because it involved assignment to dose, during which total nightly doses up to 9 g per night were administered without titration.2
TEAEs accounted for ∼50% of discontinuations in these studies. Real-world data suggest that ∼26–35% of patients using SXB discontinue treatment,9,10 with AEs reported as the reason for discontinuation in 10–27% of all patients.9–11 A substantial proportion of treatment discontinuations are attributable to reasons other than TEAEs. Other factors, including health insurance coverage and patient preference, may also influence discontinuations of SXB treatment.12
A strength of this research is the side-by-side presentation of data from 2 clinical trials of SXB with different study designs. Presenting the data independently, rather than pooled, allowed elucidation of the TEAE profiles associated with different dosing and titration regimens. Of particular note, the initiation dose and titration schedule administered in SXB-15 were consistent with those recommended in the prescribing information.1 Thus, the incidence and duration of TEAEs in this study may be relevant to real-world use of SXB. However, due to the controlled conditions of a clinical trial, the findings from that study may differ from those typically observed in clinical practice.
The analyses conducted also had several limitations. A large proportion of participants in SXB-15 were taking concomitant stimulant medication. All participants in SXB-22 were taking modafinil at study entry, and then randomized to maintain modafinil treatment alone, maintain modafinil treatment and initiate SXB treatment, or discontinue modafinil and initiate SXB treatment. Concomitant use or discontinuation of other medications may have confounded AE reporting or interpretation of AE findings. Further, clinical trial methodology limits the certainty of AE duration. More specifically, in both of the analyzed clinical trials, information regarding TEAEs was collected through participant self-report at prescheduled clinic visits. As a result, reporting accuracy for dates of onset and resolution of TEAEs may be affected by participant recall, frequency of scheduled study visits, and failure to document AE resolution.
In conclusion, early-onset TEAEs associated with SXB treatment included dizziness, nausea, and headache; incidence of new or worsened early-onset TEAEs diminished over time. These analyses may inform clinician expectations regarding the type, time course, and duration of common early-onset TEAEs associated with SXB treatment. The findings also demonstrate the importance of individualized, gradual titration of SXB dose and regimen to optimize efficacy and tolerability in SXB-treated patients.
DISCLOSURE STATEMENT
All authors have reviewed and approved this manuscript. This study was funded by Jazz Pharmaceuticals. Under the direction of the authors, Melinda Ramsey, PhD, and Hannah Ritchie, PhD, of Peloton Advantage, LLC, an OPEN Health company, provided medical writing assistance for this publication, which was funded by Jazz Pharmaceuticals. A.M.H. has received research funding from UCB and Marinus Pharmaceuticals; consultancy fees from Marinus Pharmaceuticals, Sage Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Eisai, Neurelis Pharmaceuticals, and UCB; publisher compensation from Wolters Kluwer, Demos, and Springer; and honoraria from University at Sea, MER, and Eisai. S.B., R.R., B.S., and J.P. are employees of Jazz Pharmaceuticals who, in the course of this employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. J.B. is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals plc. All relevant data are provided within the manuscript and supporting files.
ACKNOWLEDGMENTS
The authors thank the study team and patients for their participation in this research.
ABBREVIATIONS
- AE
adverse event
- SXB
sodium oxybate
- TEAE
treatment-emergent adverse event
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