Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy

3.1 Participant Disposition

Overall, the safety population comprised 201 participants (SXB alone, n = 52; SXB with other anticataplectics, n = 23; other anticataplectics alone, n = 36; anticataplectic-treatment naive n = 90) assessed between 14 March 2017 and 10 July 2019. The median (range) age was 36 (18–70) years, 61% were female, and 88% were White. Participants had a mean (SD) body mass index (BMI) of 28.8 (6.1) kg/m2 (n = 199; baseline BMI values could not be determined for two participants due to missing height measurements). Full demographics and baseline disease characteristics for the safety population have been reported previously [10].

Seventy-four participants enrolled in the subsequent OLE (Table 1); 27 re-entered (after a median (range) of 15.0 (4.0–33.0) days), and 47 rolled over. The median (range) age was 38.0 (18–70) years; most were female (66.2%) and White (91.9%). The majority (97.3%) of participants in the OLE had been taking twice-nightly, equally divided doses of LXB during the SDP in the main study.

Table 1 Baseline characteristics in the OLE (safety population)3.2 Timing and Duration of Treatment-Emergent Adverse Events (TEAEs) During the Open-Label Optimized Treatment and Titration Period (OLOTTP) and the Stable Dose Period (SDP)

Overall, although TEAEs varied by treatment at study entry, new TEAEs were most common during the initial weeks of the OLOTTP, had a short median duration (Table 2), and decreased in frequency as the study progressed. Few participants had TEAEs of fall (n = 2 (1%)) or enuresis (n = 7 (3%)). Participants previously taking SXB alone (Fig. 2a) reported TEAEs including headache (18 events; n = 8 (15%); median (range) duration = 1 (1–112) day) and diarrhea (4 events; n = 4 (8%); median (range) duration = 41 (2–131) days). Peak headache incidence was week 4 (n = 4/52, 8%) in this group, whereas diarrhea had no peak incidence.

Table 2 Incidence and duration of TEAEs occurring in ≥ 5% of participants during the OLOTTP and SDP (safety population)a,bFig. 2figure 2

New (top) and Continuinga (bottom) TEAEs at each week during the OLOTTP and SDP in participants taking SXB alone (a), SXB with other anticataplectics (b), other anticataplectics alone (c), and no prior anticataplectic treatment (d) (safety population). LXB low-sodium oxybate, OLOTTP open-label optimized treatment and titration period, SDP stable-dose period, SXB sodium oxybate, TEAE treatment-emergent adverse event. aIncludes all participants experiencing a TEAE at each study time point, regardless of the week of TEAE onset

Three participants previously taking SXB with other anticataplectics (n = 3 (13%)) reported three headache events, one each in weeks 1, 2, and 4 (Fig. 2b); one reported nausea (4%) persisting from week 1 to week 8. This group had the highest rate of cataplexy, which persisted throughout the duration of the OLOTTP and SDP.

Participants previously taking other anticataplectics alone (Fig. 2c) reported TEAEs including headache (14 events; n = 7 (19%); median (range) duration = 1 (1–94) day), nausea (9 events; n = 7 (19%); median (range) duration = 3 (1–16) days), and dizziness (9 events; n = 6 (17%); median (range) duration = 4 (1–29) days). Peak incidence was week 1 (n = 3/36, 8%) for headache, week 6 (n = 2/32, 6%) for nausea, and week 4 (n = 2/33, 6%) for dizziness among this group.

Anticataplectic-treatment-naive participants reported the highest number of TEAEs (Fig. 2d), most commonly headache (36 events; n = 24 (27%); median (range) duration = 1 (1–147) day), nausea (19 events; n = 16 (18%); median (range) duration = 9 (1–37) days), and dizziness (15 events; n = 13 (14%); median (range) duration = 10 (1–117) days). Peak incidence was week 2 (n = 8/89, 9%) for headache, week 3 (n = 3/88, 3%) for dizziness, and week 1 (n = 6/90, 7%) for nausea. Several anticataplectic-treatment-naive participants (13 events; n = 12 (13%)) also reported decreased appetite, with a relatively long median duration (58 (2–358) days).

Across the entire study, 22 severe TEAEs were reported by 15 participants, 12 of whom were taking LXB at the time the severe TEAE occurred. During the OLOTTP and SDP, most TEAEs reported were mild to moderate in severity; nine participants (4%) reported 16 severe TEAEs during these periods. Severe TEAEs reported in participants taking LXB were cataplexy (n = 3, four events), headache (n = 2, two events), accidental overdose, adverse drug reaction (doxycycline), adverse drug reaction (nitrofurantoin), anxiety, back pain, confusional state, hyperhidrosis, insomnia, nausea, and viral cardiomyopathy (n = 1, one event each). In total, seven participants reported nine serious TEAEs during the entire study. In the OLOTTP and SDP, serious TEAEs were reported by four participants (three during OLOTTP; one during SDP). One participant experienced a serious TEAE of confusion and hallucinations after accidentally taking the second dose of 4.5 g of LXB shortly after the first dose of 4.5 g; this serious TEAE was deemed to be related to LXB treatment. The participant was hospitalized and discharged after symptoms resolved. The other three participants experienced serious TEAEs of peripheral nerve paresis, viral cardiomyopathy (which led to study discontinuation), and bile duct stone, none of which were determined to be related to the study drug.

3.3 Timing and Duration of Treatment-Emergent Adverse Events (TEAEs) During the Open-Label Extension (OLE)

The majority of participants reported ≥ 1 TEAE during the OLE (overall, 58%; re-entry, 59%; rollover, 57%). Although the number of participants with ≥ 1 TEAE during the OLE was similar between groups split by study entry, there were some differences in the most common TEAEs between the re-entry and rollover participants (Table 3). Figure 3 shows new and continuing TEAEs during the OLE across the total safety population. Overall the most commonly reported TEAEs, in terms of the total remaining participants at each month, were headache (14 events; n = 7, 9%; peak incidence was month 3 (n = 5/72); median (range) duration = 1 (1‒25) day), dizziness (eight events; n = 5, 7%; peak incidence was month 1 (n = 3/74); median (range) duration = 26 (1‒181) days), and nasopharyngitis (six events; n = 6, 8%; peak incidence was month 6 (n = 2/69); median (range) duration = 9 (1‒24) days). TEAEs were most prevalent in month 3 (n = 11/72 (15%) reporting a TEAE). No participant reported TEAEs of fall or enuresis; one reported a TEAE of nausea (rollover). Most TEAEs were mild or moderate; two participants had severe TEAEs, both unrelated to study drug (invasive ductal carcinoma (IDC), n = 1; dizziness, n = 1). One participant had a serious TEAE (IDC) and was therefore discontinued from the study. Few participants (14.9%) had LXB-related TEAEs, most frequently dizziness (overall, 5%; re-entry, 7%; rollover, 4%). LXB-related TEAEs were more common in participants who re-entered (re-entry, 22%; rollover, 11%).

Table 3 TEAEs occurring in two or more participants during the OLE (safety population)Fig. 3figure 3

New (a) and continuinga (b) TEAEs at each month during the OLE (safety population). LXB low-sodium oxybate, OLE open-label extension, TEAE treatment-emergent adverse event. aIncludes all participants experiencing a TEAE at each study time point, regardless of the month of TEAE onset

3.4 Study Discontinuations

Forty-six (23%) participants discontinued early from the OLOTTP (SXB alone, n = 7/52, 13%; SXB with other anticataplectics, n = 9/23, 39%; other anticataplectics alone, n = 10/36, 28%; anticataplectic-treatment naive, n = 20/90, 22%). TEAEs were the primary reason for study discontinuation during the OLOTTP (18 participants overall, including two (4%), five (22%), five (14%), and six (7%) in participants taking SXB alone, SXB with other anticataplectics, other anticataplectics alone, and those who were anticataplectic-treatment naive, respectively). Common TEAEs leading to discontinuation during the OLOTTP included cataplexy (eight events), somnolence (four events), nausea (three events), depression (four events), sleep disturbances (two events), headache (two events), and anxiety (two events). Other reasons included protocol deviation (n = 8), withdrawal by participant (n = 6), noncompliance (n = 4), investigator decision (n = 3), lost to follow-up (n = 3), sponsor decision (n = 2), lack of efficacy (n = 1), and other (n = 1; without additional information). An additional 21 participants discontinued prior to receiving randomized study drug in the DBRWP, including six who completed the OLOTTP but did not enter the SDP; five who discontinued early from the SDP [for reasons including protocol deviation (n = 3), TEAE (n = 1), and lost to follow-up (n = 1)]; eight who completed the SDP but did not enter the DBRWP; and two who entered the DBRWP but did not take the study drug due to randomization errors. Across the entire main study period (defined as on or after the first dose of study drug up to the first day of the OLE for rollover participants, or the day of the last dose of study drug in the DBRWP + 30 days (whichever was the earliest) for re-entry participants), common TEAEs that led to discontinuation included cataplexy (n = 7), headache (n = 2), nausea (n = 3), and psychiatric disorders such as anxiety (n = 2), depression (n = 2), depressed mood (n = 2), and irritability (n = 2).

Seven participants discontinued from the OLE (re-entry, n = 2; rollover, n = 5), three of which were because of TEAEs (IDC, n = 1; apathy, n = 1; sleep apnea syndrome, n = 1). Among these TEAEs, only apathy was considered treatment related.

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