Identifying clinically important difference on the Epworth Sleepiness Scale: results from a narcolepsy clinical trial of JZP-110.

BACKGROUND: While scores ≤10 on the Epworth Sleepiness Scale (ESS) are within the normal range, the reduction in elevated ESS score that is clinically meaningful in patients with narcolepsy has not been established. METHODS: This post hoc analysis of a clinical trial of patients with narcolepsy evaluated correlations between Patient Global Impression of Change (PGI-C) and ESS. Data of adult patients with narcolepsy from a double-blind, 12-week placebo-controlled study of JZP-110, a wake-promoting agent, were used in this analysis. Descriptive statistics and receiver operating characteristic (ROC) analysis compared PGI-C (anchor measure) to percent change from baseline in ESS to establish the responder criterion from patients taking either placebo or JZP-110 (treatments). RESULTS: At week 12, patients (n = 10) who reported being "very much improved" on the PGI-C had a mean 76.7% reduction in ESS score, and patients (n = 33) who reported being "much improved" on the PGI-C had a mean 49.1% reduction in ESS score. ROC analysis showed that patients who improved were almost exclusively from JZP-110 treatment group, with an area-under-the-curve of 0.9, and revealed that a 25% reduction in ESS (sensitivity, 81.4%; specificity, 80.9%) may be an appropriate threshold for defining a meaningful patient response to JZP-110 and placebo. CONCLUSIONS: A ≥25% reduction in patients' subjective ESS score may be useful as a threshold to identify patients with narcolepsy who respond to JZP-110 treatment.

Evaluation of the effect of JZP-110 in patients with narcolepsy assessed using the Maintenance of Wakefulness Test censored to 20 minutes.

OBJECTIVE: To evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. METHODS: In a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data. RESULTS: In Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17). CONCLUSIONS: In patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data.

Effect of Oral JZP-110 (ADX-N05) on Wakefulness and Sleepiness in Adults with Narcolepsy: A Phase 2b Study.

STUDY OBJECTIVES: To evaluate the efficacy and safety of oral JZP-110, a second-generation wake-promoting agent with dopaminergic and noradrenergic activity, for treatment of impaired wakefulness and excessive sleepiness in adults with narcolepsy. METHODS: This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 28 centers in the United States. Patients were adults with narcolepsy who had baseline scores ≥ 10 on the Epworth Sleepiness Scale (ESS) and baseline sleep latency ≤ 10 min on the Maintenance of Wakefulness Test (MWT). Patients received a daily placebo (n = 49) or JZP-110 (n = 44) 150 mg/day weeks 1-4 and 300 mg/day weeks 5-12. Primary efficacy endpoints were change from baseline in average MWT sleep latency, and the Clinical Global Impression-Change (CGI-C); secondary endpoints were change from baseline in ESS score and Patient Global Impression-Change. RESULTS: Improvements were significantly greater with JZP-110 versus placebo on mean MWT sleep latency (4 w, 9.5 versus 1.4 min, P < 0.0001; 12 w, 12.8 versus 2.1 min, P < 0.0001), percentage of patients with CGI-C improvement (4 w, 80% versus 51%, P = 0.0066; 12 w, 86% versus 38%, P < 0.0001), and mean change in ESS (4 w, -5.6 versus -2.4, P = 0.0038; 12 w, -8.5 versus -2.5, P < 0.0001). Three JZP-110-treated patients (6.8%) discontinued due to adverse events (AEs). The most common AEs with JZP-110 versus placebo were insomnia (23% versus 8%), headache (16% versus 10%), nausea (14% versus 6%), diarrhea (11% versus 6%), decreased appetite (14% versus 0%), and anxiety (11% versus 0%). CONCLUSIONS: At doses of 150-300 mg/day, JZP-110 was well tolerated and significantly improved the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier NCT01681121.

Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy.

BACKGROUND: JZP-110 is a wake-promoting agent with dopaminergic and noradrenergic activity. METHODS: This double-blind, crossover study, randomized adults with narcolepsy with or without cataplexy (N = 33) to placebo or JZP-110 at 150 mg/day (weeks 1 and 3) increased to 300 mg/day (weeks 2 and 4). Patients had to have baseline Epworth Sleepiness Scale (ESS) scores ≥10 and mean sleep latencies ≤10 min on the Maintenance of Wakefulness Test (MWT). Efficacy end points included MWT sleep latency and ESS, and the percentage of patients improved on the Clinical Global Impression of Change. RESULTS: Patients were primarily male (57.6%) and white (69.7%), with a mean (standard deviation) age of 37.1 (12.4) years. At two weeks, the change in the mean MWT sleep latency was 11.8 min longer with JZP-110 than with placebo (P = 0.0002); JZP-110 resulted in greater changes in sleep latency on each MWT trial (P <0.001). For ESS, JZP-110 was more efficacious relative to placebo after 1 (P <0.0001) and two weeks (P = 0.0002); final ESS scores were 10.8 with JZP-110 and 15.2 with placebo, changes of -6.7 and -2.4, respectively. JZP-110 was generally well tolerated; the most common adverse events with JZP-110 were nausea (12%), noncardiac chest discomfort (9.1%), and headache (9.1%). CONCLUSIONS: The efficacy of JZP-110 for impaired wakefulness and excessive sleepiness was observed at 150-300 mg/day and as early as one week after initiating treatment (Clinicaltrials.gov identifier NCT01485770).

Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.

OBJECTIVE: To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic-clonic seizure or in the postictal period following a tonic-clonic or other seizure type, to assess pharmacokinetics and to assess tolerability. METHODS: An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax ); time to maximum concentration (Tmax ); and the area under the plasma concentration-time curve for time zero to last sampling time (AUC0-12 ) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed. RESULTS: Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic-clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period ≥ 5 min after a tonic-clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose. SIGNIFICANCE: Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic-clonic seizures or in the postictal periods following tonic-clonic or other seizure types.

Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.

Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.