Psychosocial outcomes of repeated treatment of seizure clusters with midazolam nasal spray: Results of a phase 3, open-label extension trial.

OBJECTIVE: To evaluate treatment satisfaction, level of anxiety, confidence about traveling with midazolam nasal spray (MDZ-NS), and health-related quality of life in patients with seizure clusters and their caregivers after repeated, intermittent use of MDZ-NS in the outpatient setting. METHODS: We analyzed the psychosocial outcome data from a phase 3, open-label extension trial (ARTEMIS-2; P261-402; NCT01529034) in patients 12 years of age and older with seizure clusters on a stable regimen of antiseizure medications. Caregivers administered MDZ-NS 5 mg when patients experienced a seizure cluster. A second dose could be given if seizures did not terminate within 10 min or recurred from 10 min to 6 h. Treatment Satisfaction Questionnaire for Medication (TSQM), the Intranasal Therapy Impact Questionnaire (ITIQ), and the Short Form-12 Health Survey version 2 (SF-12v2) were self-administered by patients and/or caregivers at prespecified visits. RESULTS: Of the one hundred and seventy-five patients enrolled in ARTEMIS-2, 161 (92.0%) received ≥ 1 dose of MDZ-NS and had a post-treatment seizure-related assessment and were included in the Efficacy Evaluable Set in this analysis, with a total of 1,998 treated seizure clusters over a median duration of 16.8 months. All TSQM scales showed improvement from the baseline of the double-blind ARTEMIS-1 trial (NCT01390220) to the last visit in ARTEMIS-2, indicating greater satisfaction with MDZ-NS across all domains, with a mean change from baseline of 8.8, 6.1, 4.3, and 6.2 for effectiveness (n = 135), side effects (n = 139), convenience (n = 139), and global satisfaction (n = 138), respectively. Change from baseline in TSQM scores generally increased with repeated MDZ-NS use. In both patients and caregivers, anxiety generally lessened with repeated MDZ-NS use, with a mean improvement in ITIQ scores in patients' anxiety since receiving MDZ-NS from 2.5 (n = 138) to 3.5 (n = 145) from visit 1 to the last visit (and from 2.6 [n = 156] to 3.6 [n = 160] for caregivers), respectively. From visit 1 (screening and enrollment in ARTEMIS-2) to visit 10 (after 16 seizure cluster episodes treated with MDZ-NS), the proportions of patients and caregivers who answered "strongly agree" or "agree" for confidence about traveling with an intranasal spray remained ≥ 79% and generally increased over repeated MDZ-NS use. Small positive mean changes in SF-12v2 scores from baseline to the last visit were observed in both patients and caregivers, respectively, for the domains of physical functioning (0.9, 1.1), role-physical (2.4, 0.3), bodily pain (1.7, 0.3), general health (0.6, 1.2), and role-emotional (2.1, 0.3), and in the physical health component (1.6, 1.0). CONCLUSION: Patients and caregivers perceived MDZ-NS favorably, with improvement from baseline on perceived effectiveness, side effects, convenience, and global satisfaction in the TSQM. This is supported by progressively lower anxiety and higher confidence levels about traveling with MDZ-NS over repeated intermittent use in the ITIQ. The positive mean changes observed in SF-12v2 scores from baseline to the last visit were small in magnitude. Limitations of this exploratory analysis include the open-label trial design and that these questionnaires have not been directly validated in epilepsy to identify clinically important changes; however, this does not mean these findings are not clinically meaningful. Overall, MDZ-NS is a socially acceptable drug device for outpatient treatment of seizure clusters that has the potential to improve quality of life and overall independence.

Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open-label extension trial.

OBJECTIVE: To evaluate safety- and seizure-related outcomes with repeated intermittent use of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). METHODS: In this open-label extension trial (ClinicalTrials.gov NCT01529034), patients aged ≥12 years and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ-NS 5 mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10 minutes or recurred within 10 minutes-6 hours. Patients were monitored for treatment-emergent adverse events (TEAEs) throughout, and the main seizure-related outcome was treatment success, defined as seizure termination within 10 minutes and no recurrence 10 minutes-6 hours after drug administration. RESULTS: Of 175 patients enrolled, 161 (92.0%) received ≥1 MDZ-NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8 months (range = 1-55.7 months). TEAEs were experienced by 40.4% of patients within 2 days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2 days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment-related nasal discomfort and somnolence. There were no patients with treatment-related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5-mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number. SIGNIFICANCE: Repeated, intermittent, acute treatment of patients experiencing SCs with MDZ-NS in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance.

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age ≥12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout. RESULTS: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced ≥1 TEAE. SIGNIFICANCE: MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile.

Pharmacokinetics, pharmacodynamics, and tolerability of USL261, midazolam nasal spray: Randomized study in healthy geriatric and non-geriatric adults.

AIM: Characterize pharmacokinetics, pharmacodynamics, and safety/tolerability of USL261 in geriatric adults to inform its potential for treating bouts of increased seizure activity. METHODS: Phase 1, randomized, double-blind, 2-way crossover study in healthy geriatric (≥65years; n=18) and non-geriatric (18-40years; n=12) adults evaluated single USL261 doses (2.5 and 5.0mg) administered intranasally. Pharmacokinetic parameters were estimated for midazolam and 1-hydroxymidazolam (active metabolite), including area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and half-life (t1/2). Stanford Sleepiness Scale and Observer's Assessment of Alertness/Sedation assessed sedation; Digit-Symbol Substitution Test assessed psychomotor performance. RESULTS: Midazolam exposure and plasma concentrations were higher in geriatric versus non-geriatric adults (geometric mean AUC0-∞ [ng*h/mL] 2.5mg: 70 vs 54, respectively; 5.0mg: 157 vs 110; Cmax [ng/mL] 2.5mg: 27.1 vs 22.5; 5.0mg: 55.8 vs 46.1). USL261 was rapidly absorbed, with no differences in median Tmax (14.5-17.3min); mean t1/2 was longer in geriatric subjects. Similar age-related trends were observed for 1-hydroxymidazolam. Mean maximum observed pharmacodynamic effects were not significantly different between age groups, though were more pronounced following 5.0 versus 2.5mg (P<.05); return to baseline was generally achieved within 4h. USL261 was generally well tolerated, with similar adverse event rates between age groups. CONCLUSIONS: Despite increased midazolam exposure in geriatric subjects, there were no differences between age groups in pharmacodynamic effects or adverse event rates. USL261 was rapidly absorbed and pharmacodynamic effects returned to baseline within ~4h, regardless of age. Dose-dependent pharmacokinetic and maximum pharmacodynamic effects were observed. Overall, pharmacokinetic findings for USL261 were similar to studies evaluating intravenous midazolam, whereas pharmacodynamic effects were less pronounced in the elderly than previously reported.

Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study.

Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.

Enhanced induction of cytochrome P450 enzymes and CAR binding in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice following phenobarbital treatment.

Phenobarbital (PB) is a well characterized inducer of cytochrome P450 (P450) 2B and 3A subfamilies. Several proinflammatory cytokines have been shown to negatively modulate the induction of P450 by PB. In addition, PB is known to elicit an inflammatory mitogenic effect on the liver. To date, no studies have evaluated the PB induction profile of hepatic P450 in the absence of an intact tumor necrosis factor-alpha (TNFalpha) response. To test the hypothesis that endogenous TNFalpha signaling modulates hepatic P450 induction by PB in vivo, PB induction was examined in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice (ko-TNF) and wild-type mice (wt-TNF). CYP2B- and CYP3A-associated activities and protein content were induced to a significantly greater extent (p < 0.05) in ko-TNF mice compared with wt-TNF mice. In parallel with enhanced CYP2B induction, an apparent elevation in the nuclear accumulation of the principal regulatory protein for transcription of CYP2B genes, the constitutively activated receptor (CAR), was detected in ko-TNF nuclear extracts following PB treatment. Additionally, nuclear factor kappa-B binding was induced by PB in wt-TNF mice, but not in ko-TNF mice, indicating that the hepatic inflammatory response following PB treatment differed between wt-TNF and ko-TNF mice. These data demonstrate that endogenous TNFalpha signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNFalpha signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation.