495 Efficacy of Lower-Sodium Oxybate on Idiopathic Hypersomnia, Measured by the Idiopathic Hypersomnia Severity Scale

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure. Methods Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint. Results The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference [95% CI], −12.0 [−15.0, −8.0]; significant P<0.0001), component I scores (LS mean difference [95% CI], −3.9 [−4.9, −2.9]; nominal P<0.0001), and component II scores (LS mean difference [95% CI], −7.8 [−9.6, −5.9]; nominal P<0.0001). Results on all individual IHSS items reflected an improvement with LXB treatment over time during OLTTOP, which remained consistent during SDP. Conclusion These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS. Support (if any) Jazz Pharmaceuticals

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485 Efficacy and Safety of Once- and Twice-Nightly Dosing of Lower-Sodium Oxybate in Adults With Idiopathic Hypersomnia

SLEEP ◽

10.1093/sleep/zsab072.484 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A191-A192

Author(s):

Isabelle Arnulf ◽

Anne Marie Morse ◽

Patricia Chandler ◽

Rupa Parvataneni ◽

Dan Chen ◽

...

Keyword(s):

Sodium Oxybate ◽

Mean Difference ◽

Controlled Study ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Patient Global Impression ◽

Idiopathic Hypersomnia ◽

Secondary Endpoints ◽

Global Impression Of Change

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder. In a randomized, controlled study of lower-sodium oxybate (LXB; Xywav™) in adults with IH (NCT03533114), significant differences for LXB compared with placebo were observed in Epworth Sleepiness Scale (ESS; primary efficacy endpoint), self-reported Patient Global Impression of Change (PGIc), and IH Severity Scale (IHSS; key secondary endpoints). In this clinical study, investigators were permitted to initiate LXB dosing on a once-nightly or twice-nightly regimen. Methods Eligible participants aged 18–75 years began LXB treatment, administered once or twice nightly during an open-label treatment/titration and optimization period (OLTTOP; 10–14 weeks); dose amount/regimen could be adjusted during this period. Participants next entered a 2-week, open-label, stable-dose period (SDP), then were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). P values are nominal for this exploratory analysis. Results Of 154 enrolled participants, 40 (26%) initiated LXB treatment on a once-nightly regimen. In the efficacy population (n=115), 27 participants were on a once-nightly regimen during SDP (48.1% of whom initiated treatment once nightly during OLTTOP) and 88 participants were on a twice-nightly regimen during SDP (86.4% of whom initiated treatment twice nightly during OLTTOP). During SDP, median (min, max) LXB total dose was 4.5 (2.5, 6) g/night (once-nightly group) and 7.5 (4.5, 9) g/night (twice-nightly group). ESS scores worsened in participants randomized to placebo vs those continuing LXB in the once-nightly group (n=11 and n=15, respectively; LS mean difference [95% CI]: −4.93 [−7.41, −2.46]; P=0.0004) and twice-nightly group (n=47 and n=41, respectively; LS mean difference [95% CI]: −7.44 [−9.15, −5.72]; P<0.0001). Worsening was also observed in PGIc (once-nightly: 81.8% [placebo] vs 26.7% [LXB]; P=0.0077; twice-nightly: 89.4% [placebo] vs 19.5% [LXB]; P<0.0001) and IHSS score (estimated median difference [95% CI], once-nightly: −9.00 [−16.0, −3.0]; P=0.0028; twice-nightly: −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion The efficacy and safety of LXB in IH were demonstrated for both once-nightly and twice-nightly regimens. The majority of participants initiated and remained on a twice-nightly regimen. Support (if any) Jazz Pharmaceuticals

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487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study

SLEEP ◽

10.1093/sleep/zsab072.486 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A192-A192

Author(s):

Richard Bogan ◽

Yves Dauvilliers ◽

Michael Thorpy ◽

Patricia Chandler ◽

Abby Chen ◽

...

Keyword(s):

Motor Coordination ◽

Sodium Oxybate ◽

Open Label ◽

Double Blind ◽

Sleep Inertia ◽

Safety Population ◽

Idiopathic Hypersomnia ◽

Waking Up ◽

Intent To Treat ◽

Treat Population

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P<0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

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494 Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of Lower-Sodium Oxybate in Adults With Idiopathic Hypersomnia

SLEEP ◽

10.1093/sleep/zsab072.493 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A195-A195

Author(s):

Yves Dauvilliers ◽

Isabelle Arnulf ◽

Nancy Foldvary-Schaefer ◽

Patricia Chandler ◽

Rupa Parvataneni ◽

...

Keyword(s):

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Study Drug ◽

Sodium Oxybate ◽

Open Label ◽

Double Blind ◽

Sleep Inertia ◽

Idiopathic Hypersomnia ◽

Secondary Endpoints ◽

Global Impression Of Change

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. No US/EU medication is approved for treatment of IH. Lower-sodium oxybate (LXB; Xywav™; previously designated JZP-258) is a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®). The efficacy and safety of LXB was evaluated in adults with IH. Methods Eligible participants aged 18–75 years with IH began once- or twice-nightly LXB treatment entering an open-label titration and optimization period (10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP); they were then randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score; key secondary endpoints were proportion of participants who reported worsening (minimally/much/very much worse) on Patient Global Impression of Change (PGIc) and change in Idiopathic Hypersomnia Severity Scale (IHSS) score, all from end of SDP to end of DBRWP. Results The study enrolled 154 participants (mean±SD age, 40±14 years; 68% female; mean±SD ESS, 16±3.6); mean±SD dose was 6.0±1.6 g/night. Mean±SD ESS score (n=115) decreased over open-label titration/optimization (15.7±3.8 at baseline, 9.8±4.5 at week 4, and 6.1±4.0 at the end of the SDP). At the end of the DBRWP, significant worsening was observed in participants randomized to placebo, compared with maintenance of improvement in participants randomized to continue LXB, in ESS scores (n=115; LS mean difference [95% CI] in change from SDP, −6.51 [−7.99, −5.03]; P<0.0001), in the PGIc (88.1% for placebo vs 21.4% for LXB; P<0.0001), and in IHSS scores (estimated median difference [95% CI], −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events (AEs) included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Serious AEs occurred in 4 participants (non-cardiac chest pain, rhabdomyolysis, syncope, and nephrolithiasis/pyelonephritis); none were reported related to study drug. Conclusion In participants with IH, LXB demonstrated a clinically meaningful effect on excessive daytime sleepiness, self-reported global change, and overall IH symptom severity. The overall safety profile was consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals

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Tasimelteon safely and effectively improves sleep in Smith–Magenis syndrome: a double-blind randomized trial followed by an open-label extension

Genetics in Medicine ◽

10.1038/s41436-021-01282-y ◽

2021 ◽

Author(s):

Christos M. Polymeropoulos ◽

Justin Brooks ◽

Emily L. Czeisler ◽

Michaela A. Fisher ◽

Mary M. Gibson ◽

...

Keyword(s):

Sleep Quality ◽

Crossover Study ◽

Total Sleep Time ◽

Sleep Time ◽

Open Label ◽

Double Blind ◽

Open Label Study ◽

Label Study ◽

Sleep Complaints ◽

Open Label Extension

Abstract Purpose To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.

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489 Pivotal Phase 3 Study of FT218, a Once-Nightly Sodium Oxybate Formulation, in Patients With Narcolepsy: REST-ON Primary Results

SLEEP ◽

10.1093/sleep/zsab072.488 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A193-A193

Author(s):

Clete Kushida ◽

Colin Shapiro ◽

Thomas Roth ◽

Michael Thorpy ◽

Russell Rosenberg ◽

...

Keyword(s):

Adverse Reactions ◽

Sleep Latency ◽

Sodium Oxybate ◽

Mean Difference ◽

Pivotal Phase ◽

Double Blind ◽

Old Patients ◽

Maintenance Of Wakefulness Test ◽

To Receive ◽

Clinical Global Impression Improvement

Abstract Introduction Sodium oxybate (SO) is an effective treatment for patients with narcolepsy; however, currently available SO formulations require twice-nightly dosing. The purpose of this study was to evaluate efficacy and safety of FT218, an investigational once-nightly controlled-release SO formulation, for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy types 1 (NT1) and 2 (NT2). Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Coprimary endpoints were mean sleep latency (minutes) on maintenance of wakefulness test (MWT), Clinical Global Impression-Improvement (CGI-I) of sleepiness, and weekly number of cataplexy attacks (NCAs; NT1 only). Results A total of 212 patients were randomized and received study treatment (FT218, n=107; placebo, n=105). FT218 showed significant (P<0.001) improvement vs placebo in mean sleep latency on MWT for all evaluated doses; LS mean difference (minutes) between FT218 and placebo was 6.13 at 9.0 g (week 13), 6.21 at 7.5 g (week 8), and 4.98 at 6.0 g (week 3). A higher proportion of patients receiving FT218 were much/very much improved on CGI-I vs placebo (72% vs 31.6% at 9.0 g; 62.6% vs 22.8% at 7.5 g; and 40.1% vs 6.1% at 6.0 g; all P<0.001). LS mean difference between FT218 and placebo in mean weekly NCAs was significant (P<0.001) for all doses: −6.65 at 9.0 g, −6.27 at 7.5 g, and −4.83 at 6.0 g. The most common adverse reactions were nausea, vomiting, headache, dizziness, enuresis, and decreased appetite. Conclusion All evaluated doses of FT218 showed significant improvement vs placebo in mean sleep latency on MWT, CGI-I, and weekly NCAs. FT218 was generally well tolerated and the most common adverse events were consistent with known side effects of SO. Support (if any) Avadel Pharmaceuticals.

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Efficacy and safety of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain

Journal of Opioid Management ◽

10.5055/jom.2015.0304 ◽

2015 ◽

Vol 11 (6) ◽

pp. 507 ◽

Cited By ~ 8

Author(s):

Martin E. Hale, MD ◽

Thomas R. Zimmerman, MD ◽

Eli Eyal, MSc ◽

Richard Malamut, MD

Keyword(s):

Low Back Pain ◽

Back Pain ◽

Extended Release ◽

Study Drug ◽

Low Back ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Drug Loss ◽

Efficacy Measure

Objective: To evaluate efficacy and safety of hydrocodone bitartrate extended-release (ER) tablets developed with CIMA® Abuse-Deterrence Technology (ADT) versus placebo in alleviating moderate-to-severe pain in patients with chronic low back pain.Design: Phase 3, randomized, double-blind study consisting of a screening period (7-14 days), open-label titration period (≤6 weeks), and double-blind treatment period (≤12 weeks).Setting: Seventy-eight US centers.Main outcome measures: Changes from baseline at week 12 in weekly average of daily worst pain intensity (WPI; primary efficacy measure), weekly average pain intensity (API; secondary efficacy measure), adverse events (AEs), and study drug loss and diversion.Results: Patients (N = 625) who entered open-label dose titration and identified the analgesic hydrocodone ER dose (30-90 mg every 12 h) providing optimal pain relief with minimal AEs were randomized to hydrocodone ER (n = 191) or placebo (n = 180) for double-blind treatment at the identified dose; 297 patients completed the study. Least squares means [SE] changes from baseline were significantly greater (worsening pain; 11-point scale) with placebo than hydrocodone ER in weekly average of daily WPI (0.74 [0.15] vs 0.11 [0.14]; p < 0.001) and weekly API (0.55 [0.14] vs −0.03 [0.12]; p < 0.001). The most common AEs with hydrocodone ER were constipation (14 percent) and nausea (10 percent). Study drug loss (≤4 percent) and diversion (≤2 percent) rates were low.Conclusions: Hydrocodone ER formulated with ADT was significantly more effective than placebo in alleviating chronic low back pain and demonstrated a safety profile consistent with that of opioids, with a low occurrence of study drug loss and diversion.

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0740 Quality of Life in Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults with Narcolepsy with Cataplexy

SLEEP ◽

10.1093/sleep/zsaa056.736 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A281-A282

Author(s):

N Foldvary-Schaefer ◽

M J Thorpy ◽

Y Dauvilliers ◽

A Roy ◽

L Tang ◽

...

Keyword(s):

Quality Of Life ◽

Short Form ◽

Standard Of Care ◽

Sodium Oxybate ◽

Self Report ◽

Double Blind Study ◽

Open Label ◽

Double Blind ◽

Sf 36

Abstract Introduction Narcolepsy negatively impacts health-related quality of life (HRQoL). Sodium oxybate is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. Efficacy and safety of JZP-258 were established in a double-blind randomized withdrawal study in adults with narcolepsy with cataplexy. Methods Participants 18-70 years of age began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period, followed by a 2-week stable-dose period (SDP). Participants were then randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). HRQoL assessments included the 36-Item Short Form Health Survey Version 2 (SF-36) and 5-level EuroQoL 5-Dimensions Self-Report Questionnaire (EQ-5D-5L). Results 201 participants enrolled; 134 were randomized and received at least 1 dose of double-blind study medication (efficacy population; placebo, n=65; JZP-258, n=69). Decreased scores (worsening) were observed in participants randomized to placebo compared with participants randomized to continue JZP-258 treatment for the SF-36 physical component summary (median [Q1, Q3], −1.92 [−3.46, 1.73] for placebo and −0.03 [−2.07, 2.41] for JZP-258; nominal P=0.02), SF-36 mental component summary (−1.92 [−6.28, 1.34] for placebo and 1.55 [−1.88, 3.78] for JZP-258; nominal P=0.03), and EQ-5D-5L visual analog scale (−5.00 [−10.0, 5.00] for placebo and 0 [0, 5.00] for JZP-258; nominal P=0.01). No change was observed in the EQ-5D-5L crosswalk index (0 [−0.05, 0.03] for placebo and 0 [−0.01, 0.03] for JZP-258; nominal P=0.39). The overall safety profile of JZP-258 was similar to sodium oxybate. Conclusion HRQoL worsened in those randomized to placebo during DBRWP but remained stable in participants who continued JZP-258 treatment. Support Jazz Pharmaceuticals

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Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy

SLEEP ◽

10.1093/sleep/zsaa206 ◽

2020 ◽

Cited By ~ 1

Author(s):

Richard K Bogan ◽

Michael J Thorpy ◽

Yves Dauvilliers ◽

Markku Partinen ◽

Rafael Del Rio Villegas ◽

...

Keyword(s):

Placebo Group ◽

Group Versus ◽

Sodium Oxybate ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Clinical Trial Registration ◽

Titration Period ◽

Secondary Efficacy Endpoint ◽

Optimized Treatment

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.

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