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

Abstract

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.

BRIEF SUMMARY

Current Knowledge/Study Rationale: Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients were evaluated during an open-label period that followed the double-blind, placebo-controlled, randomized withdrawal period of a clinical study in 106 children and adolescents. Results of the main study were published previously.

Study Impact: The results from the open-label period demonstrated sustained efficacy of sodium oxybate up to 1 year. Safety and tolerability were consistent with studies in adults, with no unexpected safety concerns. Results of this ≤1-year study are important for understanding the long-term treatment effects and safety profile of sodium oxybate in pediatric patients with narcolepsy with cataplexy.

INTRODUCTION

Narcolepsy is a lifelong neurologic disorder with the onset of symptoms commonly occurring in childhood or adolescence.^1–3 Estimated prevalence is between 0.02% and 0.18% in North America and Western Europe.⁴ Key symptoms include cataplexy (defined as “more than one episode of generally brief [< 2 minutes], usually bilaterally symmetrical sudden loss of muscle tone with retained consciousness”) and excessive daytime sleepiness (EDS); associated features include sleep-related hallucinations, sleep paralysis, and disrupted nighttime sleep.^4,5 Narcolepsy confers a substantial burden on adult and pediatric patients, their families, and health care systems.^6–8 Cataplexy may be triggered by emotional experiences, especially positive ones such as laughter and elation,⁹ and is one of the symptoms with the greatest impact on the life of patients with narcolepsy.¹⁰ Patients with narcolepsy with cataplexy commonly report limitations in being able to express emotions freely, exercise or play sports, socialize, and perform well at work or school.¹⁰

Treatment of narcolepsy with cataplexy is symptomatic and long term.¹¹ Traditional stimulants, wake-promoting agents, and antidepressants have been used to treat narcolepsy symptoms in pediatric patients without adequate efficacy and safety data or clinical trial experience to inform pediatric dosing.^11–13 Sodium oxybate (SXB) has been approved for the treatment of EDS or cataplexy in adults with narcolepsy in the United States.¹⁴ Following the demonstration of the efficacy and safety of SXB for the treatment of cataplexy and EDS in pediatric narcolepsy in a phase 3 double-blind, placebo-controlled, randomized withdrawal study, as previously reported,¹⁵ approval of SXB was extended in 2018 to the treatment of patients 7 years of age and older.¹⁴ Prior to the present report, the long-term maintenance of efficacy and safety of SXB in pediatric narcolepsy had been described only in a smaller number of participants in individual case reports and retrospective case series,^16–21 and in 1 open-label study in adolescents.²²

Here, we report on the maintenance of efficacy and safety of SXB with long-term exposure during the open-label period (OLP; up to 47 weeks) that followed the double-blind, placebo-controlled, randomized withdrawal period of the aforementioned phase 3 study.¹⁵

METHODS

Study design

This multicenter study (30 sites in 5 countries), with a total study duration of up to 1 year, was conducted to evaluate the efficacy and safety of SXB in pediatric participants with narcolepsy with cataplexy. At study entry, participants either were taking SXB or were SXB naive. SXB-naive participants entered a dose-titration period of 3–10 weeks, then entered a 2-week stable-dose period (SDP). Participants already taking SXB entered a 3-week SDP at their established dose, giving them 1 week to familiarize themselves with the assessment diary. Following the SDP, participants were randomized 1:1 to either continue SXB treatment or take placebo during a double-blind randomized withdrawal period (DBRWP). Following the DBRWP, participants entered the OLP for up to 47 weeks. As a result of a preplanned interim analysis demonstrating positive efficacy, randomization to placebo during the DBRWP was discontinued, after which all participants received open-label SXB.¹⁵

Results from the DBRWP were reported previously.¹⁵ Efficacy and safety in the OLP are reported here. Compliance with study treatment was assessed via participant diaries and by recording the volume of medication that was dispensed and returned to the study sites. Study procedures are described in detail elsewhere.¹⁵

The study was conducted in accordance with the Declaration of Helsinki. All participants provided assent, and parent(s)/guardian(s) provided written informed consent in accordance with local institutional review board/independent ethics committee requirements. The study schema is available in Figure 1.

Figure 1. Study design.

Dashed lines indicate removal of placebo arm in the double-blind randomized withdrawal period following the positive results from the preplanned interim analysis. ^aParticipants with ≥ 2 months on a stable dose of SXB. SXB = sodium oxybate.

Study participants

Children and adolescents (7–16 years of age) with a primary diagnosis of narcolepsy with cataplexy, according to either the second or third edition of the International Classification of Sleep Disorders,^4,23 who were on SXB treatment or were SXB naive at study entry were eligible to participate. Participants were required to have a history of at least 14 cataplexy attacks in a typical 2-week period and clinically significant EDS prior to any narcolepsy treatment.¹⁵

Key exclusion criteria included narcolepsy secondary to another medical condition, a clinically significant medical condition other than narcolepsy that could interfere with the conduct or safety of the study, evidence of sleep-disordered breathing, current suicidal risk as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS),²⁴ or previous suicide attempt, and clinically significant depression independent of narcolepsy symptoms.^15,25

Anti-cataplectic therapies other than SXB were discontinued within 1 month before screening and prohibited during the study. Participants were allowed to continue stimulant/wake-promoting therapy provided the dose and regimen remained stable in the SDP and DBRWP.¹⁵

Efficacy and safety outcome measures

Efficacy assessments included the frequency of cataplexy attacks and EDS. The number of cataplexy attacks per week was calculated from a daily cataplexy-frequency diary.²⁶ The diary was completed by the participant, with assistance from a caregiver, if needed. In addition, the median number of cataplexy-free days per week (0–7) was calculated post hoc based on daily cataplexy-frequency diaries.

EDS was evaluated using the Epworth Sleepiness Scale (ESS) for Children and Adolescents (ESS-CHAD).²⁷ The ESS-CHAD is modified from the ESS to use age-appropriate language and reflect activities in which children and adolescents are likely to participate, and is a validated measure of daytime sleepiness.^27,28 The ESS-CHAD was completed at screening; at the beginning and end of the titration period (by SXB-naive participants); at the beginning and end of the SDP; at the end of the DBRWP; at clinic visits (weeks 9, 18, 26, and 39) during the OLP; and at the end of the OLP (week 52) or early termination.

For participants in the safety population (ie, those who received at least 1 dose of study drug), adverse events were coded using the Medical Dictionary for Regulatory Activities, version 17, and summarized by system organ classes and preferred terms. Treatment-emergent adverse events (TEAEs) were summarized across the study periods in which participants received SXB (titration, SDP, DBRWP, and OLP).

At screening, the end of the DBRWP, and week 52 or early termination, physical examinations were performed, including a full examination of body systems (except for a breast and genitourinary examination other than the observational evaluation needed for Tanner stage assessment of sexual maturity). A brief neurological examination was also performed, and height and weight were measured. Age- and sex-based percentiles for height, weight, and body mass index at each assessment were determined using the 2000 Centers for Disease Control and Prevention growth charts.²⁹ Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, temperature) were assessed at each on-site visit. Laboratory evaluations for hematology, chemistry, and urinalysis were assessed at screening; the end of the DBRWP; and at week 52 or early termination. Electrocardiography was assessed at screening, the end of the DBRWP, and week 52 or early termination. Scheduled polysomnography (PSG) occurred at screening and week 52 or early termination (for participants who entered the study on SXB treatment) or at screening, end of the SDP, and week 52 or early termination (for participants who were SXB naive at study entry).

Depression, anxiety, and suicide risk were assessed at each visit, including on-site and phone visits. Risk of depression was evaluated using the Children’s Depression Inventory, Second edition Self-Report Short Version (CDI 2:SR[S]).^25,30 Risk of anxiety was evaluated using the 10-item Multidimensional Anxiety Scale for Children (MASC-10).^31,32 Higher CDI 2:SR(S) T-scores and MASC-10 T-scores indicate increased severity and/or number of symptoms. The C-SSRS was used to assess risk of suicidal ideation or behavior and self-injurious behavior without suicidal intent.²⁴ The C-SSRS is administered by a clinician and involves a series of questions with binary (yes/no) response choices, where “yes” indicates suicidal risk. The children’s version was used for participants under 12 years of age and the adult version for participants 12 years and older.

Statistical analyses

Post hoc analyses were conducted to compare change in weekly number of cataplexy attacks from baseline (last 2 weeks of the SDP) to OLP weeks 18, 26, and 39, and last week observed during the OLP between participants who were SXB-naive at study entry and participants who were taking SXB at study entry, using an analysis of covariance model with treatment as a factor and baseline count as a covariate. Change in the weekly number of cataplexy attacks is reported as median change, which is computed as follows: the arithmetic difference between the median number of cataplexy attacks at baseline and the median number of cataplexy attacks during OLP is calculated for each participant, and then the median of those changes is computed, with an associated interquartile range (ie, the range from quartile [Q] 1 [the 25th percentile] to Q3 [the 75th percentile]). These analyses were based on the safety population who took study drug in the OLP. Due to no adjustments for multiplicity, the P values presented are nominal.

Cataplexy-free days per week were calculated post hoc using data from daily cataplexy-frequency diaries as follows: (number of days with 0 cataplexy attacks)/(number days with diary data) × 7. Any missing diary data were assumed to be missing at random. The number of days without cataplexy attacks was treated as a continuous variable. Cataplexy-free days per week during the titration period, SDP, and DBRWP are reported for the safety population (all participants who took study drug). Cataplexy-free days per week during the OLP are reported for the safety population who took study drug in the OLP.

RESULTS

Participants

Participants were enrolled from October 2014 to November 2016. Of the 106 enrolled participants, 59.4% were male, 58.5% were from the United States, and 68.9% were White; 30.2% were previously treated with SXB, and 69.8% were SXB naive. The median age was 12 years (range, 7–16 years), with 35.8% of participants in the 7- to 11-year-old and 64.2% of participants in the 12- to 17-year-old age groups. At screening, there were 8 male participants younger than 9 years of age (cutoff age for precocious puberty in boys), of whom 7 were at Tanner stage 1 and 1 was at Tanner stage ≥ 2, and 1 female participant younger than 8 years of age (cutoff age for precocious puberty in girls) who was at Tanner stage 1. At the end of the study, there were 4 male participants younger than 9 years of age, of whom 3 were at Tanner stage 1 and 1 was at Tanner stage ≥ 2, and 0 female participants younger than 8 years of age.

Median SXB exposure for participants taking SXB at study entry was 12 months (range, 2–52 months). The median number of years from time of narcolepsy diagnosis until screening was 1.2 year (range, 0–10.4 years). Most participants (52.8%) were rated by the historic Clinical Global Impression of Severity as markedly ill prior to any narcolepsy treatment.

Of the 106 enrolled participants, 95 entered the OLP and 85 (89.5%) of them completed that period. For participants not completing the OLP (n = 10), reasons included discontinuation due to a TEAE (n = 4), treatment noncompliance (n = 2), protocol violation (n = 1), investigator decision (n = 1), withdrawal of consent/assent (n = 1), and other (n = 1).

Mean (standard deviation [SD]) percentage of study drug compliance rate for the OLP (based on daily diaries capturing whether doses were taken or not) was 79.1% (20.0%), with no apparent differences by SXB status or age at study entry.

Fifty participants were taking stimulants/wake-promoting agents during the OLP, including modafinil (n = 18), methylphenidate hydrochloride (n = 17), amphetamine mixed salts (Obetrol; n = 11), armodafinil (n = 7), methylphenidate (n = 7), amphetamine sulfate (n = 1), dexamphetamine (n = 1), and lisdexamphetamine mesilate (n = 1). Among them, 39 participants had no change in stimulant dose. Of the 11 participants who had stimulant dose or medication change, 3 discontinued stimulant use during the OLP.

Maintenance of efficacy: outcomes

Cataplexy

As previously reported, during the 2-week DBRWP, participants who were randomized to placebo reported a significant increase in the number of weekly cataplexy attacks compared with participants who continued SXB (Figure 2).¹⁵ Sustained efficacy throughout the OLP was demonstrated for weekly cataplexy attacks. The median (Q1, Q3) change in number of weekly cataplexy attacks from baseline (last 2 weeks of the SDP) to OLP week 39 was 0.0 (−2.5, 4.9) in participants who were SXB naive at study entry and 0.0 (−3.4, 2.6) in participants who were taking SXB at study entry (P = .3895); at week 52/early termination, the change in number of weekly cataplexy attacks was 0.0 (−2.5, 3.0) and 0.0 (−0.9, 1.9), respectively (P = .8900; Figure 2). Similar results were observed by age at study entry (data not shown).

Figure 2. Median change in weekly number of cataplexy attacks.

Data are shown as the change from baseline (last 2 weeks of the SDP) to the DBRWP, by randomized treatment, and to the indicated week in the OLP, by SXB status at study entry. DBRWP represents change from baseline for all days within the DBRWP. Vertical lines represent Q1 (up) and Q3 (down). The P value for the DBRWP corresponds to a comparison of participants who were randomized to placebo with participants who continued SXB (efficacy population), as reported previously.¹⁵ P values for the OLP correspond to post hoc comparisons of participants who were SXB naive at study entry with participants who were taking SXB at study entry (safety population who took study drug in the OLP); due to no adjustment for multiplicity, these P values are nominal. DBRWP = double-blind randomized withdrawal period, OLP = open-label period, Q = quartile, SDP = stable-dose period, SXB = sodium oxybate.

In SXB-naive participants, the median (Q1, Q3) number of cataplexy-free days per week (ie, days when zero cataplexy attacks were recorded by the participant) increased from 0.0 (0.0, 2.0) at study entry to 4.0 (1.0, 6.0) at the end of the titration period (Figure 3A). By the end of the SDP, the median (Q1, Q3) number of cataplexy-free days per week in participants who were SXB naive at study entry was similar to that in participants taking SXB at study entry (4.3 [1.0, 5.8], n = 66; and 4.8 [0.8, 6.5], n = 32, respectively). During the DBRWP, the median (Q1, Q3) number of cataplexy-free days per week decreased to 0.0 (0.0, 2.6) in participants randomized to placebo (n = 32), indicating that a majority of these participants were again experiencing daily cataplexy attacks within 2 weeks of SXB treatment discontinuation; in contrast, the number of cataplexy-free days was stable at 4.0 (1.0, 6.0) in participants who continued SXB treatment (n = 31; Figure 3B). During the OLP, the number of cataplexy-free days per week remained stable. The median (Q1, Q3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in the first week of the OLP (n = 93) and 3.8 (0.5, 5.5) in week 48 (n = 12; Figure 3C). During the last week observed in the OLP, the median (Q1, Q3) number of cataplexy-free days was 4.7 (0.0, 7.0) in the overall population (n = 94), 4.7 (0.0, 7.0) in participants who were SXB naive at study entry (n = 62), and 5.0 (0.0, 7.0) in participants who were taking SXB at study entry (n = 32).

Figure 3. Median number of cataplexy-free days per week.

Data shown are (A) during the dose titration period for SXB-naive participants, (B) during the DBRWP in participants who were randomized from a stable dose of SXB to placebo and in participants who continued SXB, and (C) over the OLP in the total population. Because participants in the SXB-naive group were individually titrated over a period of 3–10 weeks, the duration of the OLP for each participant varied from 38 to 45 weeks (for a total study duration of up to 1 year). Thus, the number of SXB-naive participants for whom data were available decreased over weeks 38–45 as participants completed the study. Vertical lines represent Q1 (up) and Q3 (down). DBRWP = double-blind randomized withdrawal period, OLP = open-label period, Q = quartile, SDP = stable-dose period, SXB = sodium oxybate.

EDS

As previously reported,¹⁵ participants who were randomized to placebo reported statistically significant worsening of EDS, compared with participants who continued SXB treatment during the DBRWP (Figure 4). Sustained efficacy throughout the OLP was demonstrated for the treatment of EDS. The median (Q1, Q3) change in ESS-CHAD scores from baseline (the end of the SDP) to OLP week 52 was 0.0 (−3.0, 2.5) in participants who were SXB naive at study entry and 1.0 (−3.0, 3.0) in participants who were taking SXB at study entry. Similar results were observed by age at study entry (data not shown).

Figure 4. Median change in ESS-CHAD scores.

Data are shown as the change from baseline (last 2 weeks of the SDP) to the DBRWP, by randomized treatment, and to the indicated week in the OLP, by SXB status at study entry. DBRWP represents change from baseline for all days within the DBRWP. Vertical lines represent Q1 (up) and Q3 (down). The P value for the DBRWP corresponds to a comparison of participants who were randomized to placebo with participants who continued SXB (efficacy population), as reported previously.¹⁵ DBRWP = double-blind randomized withdrawal period, ESS-CHAD = Epworth Sleepiness Scale for Children and Adolescents, OLP = open-label period, Q = quartile, SDP = stable-dose period, SXB, sodium oxybate.

Safety outcomes

Two participants in the enrolled population (n = 106) did not take any dose of study drug. Of the 104 participants who received at least 1 dose of SXB, 80 (76.9%) reported TEAEs while taking SXB during all study periods; the majority were mild or moderate in severity (Table 1). TEAEs were reported by 78.4% and 76.1% of participants 7–11 and 12–17 years of age, respectively. TEAEs were reported more frequently among participants who were SXB naive compared with participants taking SXB at study entry (83.3% and 62.5%, respectively). The most frequently reported TEAEs (≥ 5%) were enuresis (19.2%), nausea (19.2%), vomiting (18.3%), headache (17.3%), decreased weight (11.5%), decreased appetite (8.7%), nasopharyngitis (7.7%), upper respiratory tract infection (5.8%), and dizziness (7.7%).

Table 1.

TEAEs with incidence ≥ 5% during the course of the 1-year study period.

	Age 7–11 ya (n = 37)	Age 12–17 ya (n = 67)	SXB Naive at Study Entryb (n = 72)	On SXB at Study Entryb (n = 32)	Total (n = 104)c
TEAEs, n (%)
Any TEAEs	29 (78.4)	51 (76.1)	60 (83.3)	20 (62.5)	80 (76.9)
Any serious TEAEs	0	2 (3.0)	2 (2.8)	0	2 (1.9)
Any TEAEs leading to  study withdrawal	1 (2.7)	5 (7.5)	6 (8.3)	0	6 (5.8)
TEAEs in ≥ 5% of total participants, n (%)
Enuresis	8 (21.6)	12 (17.9)	16 (22.2)	4 (12.5)	20 (19.2)
Nausea	6 (16.2)	14 (20.9)	18 (25.0)	2 (6.3)	20 (19.2)
Vomiting	10 (27.0)	9 (13.4)	17 (23.6)	2 (6.3)	19 (18.3)
Headache	5 (13.5)	13 (19.4)	14 (19.4)	4 (12.5)	18 (17.3)
Weight decreased	5 (13.5)	7 (10.4)	11 (15.3)	1 (3.1)	12 (11.5)
Decreased appetite	2 (5.4)	7 (10.4)	9 (12.5)	0	9 (8.7)
Nasopharyngitis	3 (8.1)	5 (7.5)	7 (9.7)	1 (3.1)	8 (7.7)
Upper respiratory tract  infection	2 (5.4)	4 (6.0)	5 (6.9)	1 (3.1)	6 (5.8)
Dizziness	2 (5.4)	6 (9.0)	7 (9.7)	1 (3.1)	8 (7.7)

Data are number of participants (%). Events listed occurred in ≥ 5% of the total safety population and were measured during all study periods in which participants were receiving SXB. TEAEs reported by preferred term exclude events occurring in the double-blind period for participants receiving placebo. ^aAge at first dispense of study drug. ^bSXB status at study entry. ^cOf 106 participants in the enrolled population (all participants who were dispensed study drug), 2 participants did not receive study drug. SXB = sodium oxybate, TEAE = treatment-emergent adverse event.

Across all study periods, 6 TEAEs led to study discontinuation, including headache, myalgia, sleep apnea syndrome, suicidal ideation, tactile hallucination, and decreased weight (headache and myalgia were in the same participant). During the titration period, there were 2 serious TEAEs (SAEs): 1 participant (suicidal ideation, which resolved on discontinuation of SXB) was terminated from the study and 1 participant (acute psychosis) continued in the study following symptom resolution.

Increased central sleep apnea (CSA) index (CAI) in some participants was identified during scheduled PSG in the study. TEAEs of sleep apnea syndrome, associated with an increased CAI (> 10 events/h of sleep) on PSG, were reported in 2 participants; these TEAEs occurred in 1 case at the start of the DBRWP and in 1 case during the OLP. In both cases, increased CAIs occurred primarily after the second nightly dose of SXB. The first case was an 8-year-old male who was SXB naive at study entry. An increased CAI was noted on PSG at the end of the SDP (CAI, 36.5; brief desaturation to 83%) at a total nightly dose of 6 g SXB. CSA events were noted on repeat PSG at a total nightly dose of 4.5 g SXB 6 days later (CAI unavailable) and on another repeat PSG with 4 g SXB 15 days after the first repeat PSG (CAI, 23.9; brief desaturation to 88%). SXB was discontinued, and the participant was withdrawn from study participation. On follow-up PSG 6 days later, while not taking SXB treatment, no CSA was detected. Two months later, another follow-up PSG was conducted with the participant taking a total nightly dose of 3.75 g SXB, during which the CAI was recorded as 0.6 (which is considered normal). The second case was a 14-year-old female taking SXB at study entry. CSA (CAI, 16.1) was observed on PSG at the end of the OLP at a total nightly dose of 7 g SXB but not on repeat PSG 15 months later (CAI, 0.3) at 6.5 g SXB.

There was minimal change in depression and anxiety risk overall (CDI 2:SR[S] and MASC-10 results) over time. Mean CDI 2:SR(S) T-scores remained within the average-risk range (T-scores of 41–59) throughout the study, with a slight initial trend toward improvement from the start of titration to the start of the SDP, which then stabilized and remained stable throughout the study. Mean (SD) CDI 2:SR(S) T-score at baseline was 50.4 (7.4), with 11.5% of participants in the low-risk range (T-scores of ≤ 40) and 73.1% in the average-risk range. At week 52, the mean (SD) CDI 2:SR(S) T-score was 45.7 (6.7), with 36.6% of participants in the low-risk range and 56.1% in the average-risk range. Results were similar by SXB status (Figure 5A) or age at study entry (data not shown). Mean MASC-10 T-scores remained stable and within the average-risk range (T-scores of 40–55) throughout the study. Mean (SD) MASC-10 T-score at baseline was 49.0 (11.6), with 24.0% of participants in the below-average-risk (T-scores of < 40) and 43.3% in the average-risk range. At week 52, mean (SD) MASC-10 T-score was 46.7 (12.7), with 30.1% in the below-average-risk and 41.0% of participants in the average-risk range. Results were similar by SXB status (Figure 5B) or age at study entry (data not shown).

Figure 5. Mean CDI 2:SR(S) and MASC-10 T-scores.

Mean (SE) (A) CDI 2:SR(S) and (B) MASC-10 T-scores over the course of the study, by SXB status at study entry (safety population). Visits at week (W) 1, W3, W8, and W9 were not required for all participants; therefore, fewer observations were available at these time points and increased variability was observed. Time between study weeks was not equally spaced: W3 and W4 were ±3 days and W16 through W52 were ±7 days. CDI 2:SR(S) T-scores are categorized as low (≤ 40), average (41–59), high average (60–64), elevated (65–69), and very elevated (≥ 70). MASC-10 T-scores are categorized as below average (< 40), average (40–55), slightly above average (56–60), above average (61–65), much above average (66–70), and very much above average (> 70). ^aSDP was 2 weeks for SXB-naive participants and 3 weeks for participants taking SXB at study entry. ^bDBRWP was 2 weeks. ^cW9 was 4 weeks after the DBRWP. CDI 2:SR(S) = Children’s Depression Inventory, Second edition, Self-Report Short Version, D = day, DB and DBRWP = double-blind randomized withdrawal period, MASC-10 = 10-item Multidimensional Anxiety Scale for Children, OLP = open-label period, SD and SDP = stable-dose period, SE = standard error, SXB = sodium oxybate, W = week.

No participants responded “yes” to any C-SSRS item at any time, except for the 2 participants with SAEs. Of those, 1 participant, a 14-year-old White male who was SXB naive at study entry, reported suicidal ideation during the titration period (study day 3) at a total nightly dose of 4.5 g SXB (SAE, suicidal ideation). This SAE was considered moderate in severity, continuous, and related to SXB. The SAE resolved after discontinuation of SXB, and the participant was discontinued from the study. The second participant, a 13-year-old White male who was SXB naive at study entry, reported nonsuicidal self-injurious behavior during the titration period (study day 32) while treated with a total nightly dose of 8 g SXB (SAE, acute psychosis). This SAE was considered severe and related to SXB. It resolved after SXB interruption. The participant resumed SXB 2 weeks later at a lower dose (4.5 g) and continued treatment in the study. The participant completed the OLP with no recurrent event.

DISCUSSION

As narcolepsy is a chronic disorder that often begins in childhood and requires long-term treatment,^1–3 the long-term efficacy and safety of narcolepsy treatments are important to consider when selecting a medication. There have been few reports of long-term efficacy and safety of SXB in pediatric narcolepsy populations.^16–22 In the present study, the efficacy and safety of SXB for the treatment of cataplexy and EDS in pediatric narcolepsy were demonstrated in a DBRWP,¹⁵ and as shown here, long-term maintenance of efficacy and safety of SXB was shown during a ≤ 47-week OLP. These results are consistent with observations of SXB treatment in previous retrospective and open-label studies.^16–18

During the OLP, participants demonstrated sustained improvement in cataplexy frequency, cataplexy-free days, and EDS. In addition, most participants (78%) had no change to prescribed stimulants/wake-promoting agents during this period. The long-term efficacy of SXB in this pediatric population is consistent with long-term results in adults, in which cataplexy and EDS assessments continued to improve or remained stable over time.³³

Safety throughout the study was consistent with previous reports in adults,¹⁴ with no unexpected safety concerns identified. With SXB treatment, TEAEs tend to occur early and diminish over time,^14,34 which may explain why TEAEs reported in this study were fewer in participants taking SXB at study entry than in participants who were SXB naive at study entry. Throughout the course of the study, 6 participants withdrew due to TEAEs. The 2 SAEs that were reported (positive [“yes”] responses to C-SSRS items) occurred early in the study during the titration period, with no SAEs reported during the OLP. There was no evidence of precocious puberty with onset during SXB treatment, although the number of prepubescent participants entering the study was small. Participants’ height and weight during the study were not reported here but will be described elsewhere in detail.

The safety profiles of SXB in the 7–11- and 12–17-year age groups were generally similar. Incidence of enuresis was slightly higher in younger compared with older participants. Enuresis has been reported as a TEAE in a study of SXB treatment in pediatric narcolepsy,¹⁵ and TEAEs of enuresis were reported in adult studies of SXB,^34,35 albeit at lower rates. Enuresis is more prevalent in children than adults in the general population.^36,37

The prevalence of psychiatric disorders, particularly depression, is increased in adult and pediatric narcolepsy compared with controls.^38,39 Although psychiatric and behavioral TEAEs have been reported previously in adult and pediatric patients taking SXB,¹⁴ depression, anxiety, and suicidality assessments did not suggest additional concerns with long-term SXB treatment. CDI 2:SR(S) and MASC-10 mean T-scores remained within the average range throughout the study period of up to 1 year. There was an initial slight downward trend in observed CDI 2:SR(S) mean T-scores from the start of titration to the start of the SDP, which then stabilized and remained stable over time. Thus, for both CDI 2:SR(S) and MASC-10, there was a suggestion of improvement from T-score categories that indicated average risk initially to T-score categories that indicated low or below-average risk, respectively, at study end. The positive C-SSRS responses in 2 SXB-naive participants occurred during titration, with no incidences of positive response for suicide risk in participants during the OLP. In both participants, symptoms resolved on discontinuation of SXB, and 1 participant restarted SXB at a lower dose and continued the study without reoccurrence of symptoms. As noted in the SXB prescribing information, it is important to screen for psychiatric symptoms at initiation of SXB and throughout treatment.¹⁴

Recently, a validated instrument was developed for quantifying the frequency, severity, and consequences of symptoms of narcolepsy type 1 in children 10 years of age and older.⁴⁰ The Pediatric Narcolepsy Severity Scale (NSS-P), a modified version of the adult Narcolepsy Severity Scale (NSS), is sensitive to changes in symptoms following narcolepsy treatment.⁴⁰ In future clinical studies on narcolepsy in pediatric populations, the NSS-P may be useful as an efficacy outcome measure.

At the maximum recommended dosages for pediatric patients 7 years of age and older (6–9 g/night), SXB contributes 1,100–1,640 mg to total daily sodium intake.¹⁴ Increased sodium intake is associated with greater risk of hypertension and adverse cardiovascular outcomes.^41–43 As narcolepsy is a chronic condition that often manifests in childhood or adolescence,^1–3 young patients may be at risk of negative long-term health consequences with increased sodium exposure associated with lifelong treatment with SXB. Lower-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates) is an oxybate medication that contains the same active moiety as SXB but with a unique composition of cations resulting in 92% less sodium.⁴⁴ LXB was approved by the US Food and Drug Administration for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy, and for the treatment of idiopathic hypersomnia in adults.⁴⁵ Recently, the Food and Drug Administration recognized the historical use of SXB in narcolepsy, but determined that LXB is clinically superior to SXB due to its significant reduction in chronic sodium burden compared with LXB, as well as the impact of that reduction on long-term health and cardiovascular morbidities in a substantial proportion of patients for whom LXB is indicated.⁴⁶

Limitations

This study included participants in younger and older age groups and participants who were already taking SXB or were SXB naive at study entry. A limitation of the study is the smaller sample size in the 7- to 11-year-old age group relative to the 12- to 17-year-old age group.

CONCLUSIONS

The results presented here on long-term treatment effects of SXB on cataplexy and EDS in children and adolescents with narcolepsy with cataplexy, a chronic disorder, complement the previously published main findings of this trial.¹⁵ Evaluation of long-term SXB treatment for up to 1 year in this population demonstrated maintenance of efficacy for EDS and cataplexy and a safety profile that was similar overall to previous studies performed in adults, with no unexpected safety concerns identified. The safety profiles of SXB in participants aged 7–11 and 12–17 years were generally similar, with enuresis, nausea, vomiting, headache, decreased weight, and decreased appetite reported by ≥ 10% of participants in either age group. These results provide important information about SXB long-term treatment for clinicians who treat children and adolescents with narcolepsy.

ABBREVIATIONS

CAI

central sleep apnea index

CDI 2:SR(S)

Children’s Depression Inventory, Second edition, Self-Report Short Version

CSA

central sleep apnea

C-SSRS

Columbia-Suicide Severity Rating Scale

DBRWP

double-blind randomized withdrawal period

EDS

excessive daytime sleepiness

ESS-CHAD

Epworth Sleepiness Scale for Children and Adolescents

LXB

lower-sodium oxybate

MASC-10

10-item Multidimensional Anxiety Scale for Children

NSS

Narcolepsy Severity Scale

NSS-P

Pediatric Narcolepsy Severity Scale

OLP

open-label period

PSG

polysomnography

Q

quartile

SAE

serious adverse event

SD

standard deviation

SDP

stable-dose period

SXB

sodium oxybate

TEAE

treatment-emergent adverse event

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Work for this study was funded by Jazz Pharmaceuticals. Jazz Pharmaceuticals was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Under the direction of the authors, Kirsty Nahm, MD, of the Curry Rockefeller Group, and Karyn Liu, PhD, and Michael J. Theisen, PhD, of Peloton Advantage, LLC, an OPEN Health company, provided medical writing assistance for this publication, which was funded by Jazz Pharmaceuticals. Dr. Lecendreux has participated in advisory boards for UCB Europe, NLS Pharma, Jazz Pharmaceuticals, and Bioprojet, and has received grant support from UCB Europe and Shire. Dr. Plazzi has participated in advisory boards for Bioprojet, Idorsia, Takeda, and Jazz Pharmaceuticals. Dr. Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Idorsia, Takeda, Theranexus, and Bioprojet. Dr. Rosen has received research funding from Jazz Pharmaceuticals and acknowledges the following support: “In Cleveland, this publication was made possible by the Clinical and Translational Science Collaborative of Cleveland, 4UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health (NIH) and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.” At the time of this publication, Dr. Rosen is a board member of the American Academy of Sleep Medicine. Dr. Rosen contributed to the article in her personal capacity. The views expressed are her own and do not necessarily represent the view of the American Academy of Sleep Medicine. Dr. Ruoff has served as an advisory board member and unpaid consultant for Jazz Pharmaceuticals. Dr. Black is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals plc. Ms. Parvataneni, Dr. Wang, and Dr. Guinta are former employees of Jazz Pharmaceuticals who, in the course of this employment, received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals, plc. Dr. Mignot has received research support from Jazz Pharmaceuticals, is a consultant for Dreem (a sleep consumer product) and Inoxia/Orexia (companies working on orexin agonists), and is on the speakers bureau for Vox Media. At Stanford, he is involved in clinical trials involving Huami, Takeda, Apple, Jazz Pharmaceuticals, and Sunovion.