Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study

BACKGROUND: Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. METHODS: The study enrolled patients aged 6-65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. RESULTS: Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. CONCLUSIONS: This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069

Future Opportunities for Research in Rescue Treatments

Clinical studies of rescue medications for seizure clusters are limited and are designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine the factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice for how they could enhance future trials of seizure cluster treatments. The topics addressed in this article are: (1) unaddressed end points to pursue in future studies, (2) roles for devices to enhance rescue medication clinical development programs, (3) tools to study seizure cluster prediction and prevention, (4) the value of other designs for seizure cluster studies, and (5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel end points and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on health care resources

The differential effects of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on seizure frequency in patients with drug-resistant epilepsy – A Randomized, double-blind, placebo-controlled trial

Abstract The omega-3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to play an important role in maintenance and modulation of neuronal functions. There is evidence that omega-3 fatty acids may have anticonvulsant effects. The effect of DHA and EPA on seizure rate in patients with DRE was investigated. Methods: A double-blind, randomized, placebo-controlled clinical trial included ninety-nine (n=99) DRE patients, aged 5-16 (n=85) and 17-45 (n=14). After randomization, patients were given two, four or six capsules per day of DHA (417.8 mg DHA and 50.8 mg EPA/capsule, n=33), EPA (385.6 mg EPA and 81.2 mg DHA/capsule, n=33) or placebo (high oleic acid sunflower oil, n=33) for one year. The primary endpoint was the effect of treatment on rate of seizure. Random-effects negative binomial regression models were fitted to model the patients’ total count of seizures per month. The treatment effects on seizure incidence rate ratio was tested after controlling for the covariate effects of gender, age, rate of seizure per week at enrollment, type of seizure and number of AEDs combinations used at enrollment. Results: Fifty-nine patients (n=59) completed the study (59.6%).The average number of seizures per month were 9.7 ± 1.2 in the EPA group, 11.7 ± 1.5 in the DHA group, and 16.6 ± 1.5 in the placebo group. Age, gender and seizure type adjusted seizure incidence rate ratios (IRRs) of the EPA and DHA groups compared with the placebo were 0.61 (CI= 0.42-0.88, p=0.008, 42% reduction) and 0.67 (CI = 0.46-1.0, p= 0.04, 39% reduction), respectively. There was no difference in IRR between the EPA and DHA groups (p=0.56). Both treatment groups had a significantly higher number of seizure-free days compared to placebo (p<0.05). Significance: This study demonstrates that EPA and DHA are effective in reducing seizure frequency in patients with DRE

Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study.

OBJECTIVE: Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray. METHODS: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2. RESULTS: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P \u3c 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use. CONCLUSIONS: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers

Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)–approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions

Use of intranasal rescue therapy for seizure clusters in students with epilepsy: Nurses’ knowledge, perceptions, and practice

School nurses play a crucial role in the prompt, appropriate response to epilepsy-related seizure emergencies among students in the school setting. Two intranasal benzodiazepine rescue therapies are now approved and offer potential benefits of being easy to use and socially acceptable. In July 2021, a survey was sent to 49,314 US school nurses to assess knowledge, perceptions, and practice with seizure rescue therapy. Responses were received from 866 (1.8% response rate). Of respondents, 45.7% had used rectal diazepam gel; 9.3%, midazolam nasal spray; and 6.0%, diazepam nasal spray. The majority (58.7%) had not delegated authority to administer rescue therapy, with state/local regulations and lack of willingness of school personnel being the most common barriers to delegation (37.7% and 20.1%, respectively). Additional training of nurses and school staff and progress on delegation policies may help optimize appropriate use of intranasal rescue therapy for seizures and enhance care of students with epilepsy in schools

The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters

Nasal administration of treatments for neurologic conditions, including rescue therapies to treat seizure clusters among people with epilepsy, represents a meaningful advance in patient care. Nasal anatomy and physiology underpin the multiple advantages of nasal administration but also present challenges that must be addressed in any successful nasal formulation. Nasal cavity anatomy is complex, with a modest surface area for absorption that limits the dose volume of an intranasal formulation. The mucociliary clearance mechanism and natural barriers of the nasal epithelia must be overcome for adequate absorption. An extensive vasculature and the presence of olfactory nerves in the nasal cavity enable both systemic and direct-to-brain delivery of drugs targeting the central nervous system. Two intranasal benzodiazepine rescue therapies have been approved by the US Food and Drug Administration for seizure-cluster treatment, in addition to the traditional rectal formulation. Nasal sprays are easy to use and offer the potential for quick and consistent bioavailability. This review aims to increase the clinician’s understanding of nasal anatomy and physiology and of the formulation of intranasal rescue therapies and to facilitate patient education and incorporate intranasal rescue therapies for seizure clusters (also known as acute repetitive seizures) into their seizure action plans

Anticipatory anxiety of seizures in epilepsy: A common, complex, and underrecognized phenomenon?

The diagnosis of epilepsy is associated with loss of predictability, which invariably results in the fear of when and if future seizures will occur. For a subset of patients with epilepsy (PWE), there may be a pathological persistent fear of seizure occurrence, resulting in limitations to daily activities through avoidant behaviors. Paradoxically, the research of anticipatory anxiety of seizures (AAS; also referred to as seizure phobia) has been practically nonexistent and, not surprisingly, this condition remains underrecognized by clinicians. The available data are derived from three small case series of patients followed in tertiary epilepsy centers. In this study, we review the available data on the reported clinical manifestations of AAS in PWE, and of the potential role of variables associated with it, such as personal and family psychosocial and psychiatric history and epilepsy-related variables. In addition, we review the need for the creation of screening tools to identify patients at risk of AAS and discuss potential treatment strategies, which could be considered as part of the comprehensive management for PWE

Written seizure action plans for adult patients with epilepsy: Distilling insights from emergency action plans for other chronic conditions

•Seizure emergencies can occur in adults with epilepsy on stable therapy.•Patient action plans for non–epilepsy-related conditions improve outcomes.•Seizure action plans (SAPs) promote care and safety but are underutilized in adults.•New rescue therapies and guidance on seizure clusters support the use of adult SAPs.•Concrete efforts to improve the uptake of SAPs among adults with epilepsy are needed. Seizure emergencies and potential emergencies, ranging from seizure clusters to prolonged seizure and status epilepticus, may affect adults with epilepsy despite stable antiseizure therapy. Seizure action plans (SAPs) are designed for patients and their caregivers/care partners to provide guidance on the individualized treatment plan, including response to potential seizure emergencies and appropriate use of rescue therapy. The use of pediatric SAPs is common (typically required by schools), however, most adults with epilepsy do not have a plan. Patient-centered action plans are integral to care for other chronic conditions and may offer insights applicable to the care of adults with epilepsy. This review analyzes the potential benefits of action plans for medical conditions by exploring their utility in conditions such as asthma, diabetes, chronic obstructive pulmonary disease, heart disease, and opioid overdose. Evidence across these conditions substantiates the value of action plans for patients, and the benefits of adult SAPs in epilepsy are emerging. Because wide implementation of SAPs has faced barriers, other conditions may provide insights that are relevant to implementing SAPs in epilepsy. Based on these analyses, we propose concrete steps to improve the use of SAPs among adults. A recent consensus statement promoting the use of formal SAPs in epilepsy and advances in rescue therapy delivery methods provides support to engage patients around the value of SAPs. The precedent for use of SAPs for pediatric epilepsy patients serves as the foundation to support increased usage in adults. Seizure action plans in the context of improved clinical outcomes are expected to reduce healthcare utilization, improve patient quality of life, and optimize epilepsy management

Safety, Tolerability, and Sensorimotor Effects of Extended-release Dalfampridine in Adults With Cerebral Palsy: A Pilot Study.

PURPOSE: The goal of this study was to evaluate the safety and tolerability of dalfampridine extended release (D-ER) in a pilot study of adults with cerebral palsy (CP) and limited ambulatory ability, and to explore drug effects on sensorimotor function. METHODS: An initial double-blind, single-dose crossover study was performed in 11 individuals randomized 1:1 to receive D-ER (10 mg) or placebo, followed by a 2-day washout period and the opposite treatment, with evaluation for safety and tolerability. A twice daily dosing, double-blind, placebo-controlled, crossover study was then performed. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: 1 week of D-ER (10 mg BID) or placebo, followed by a 1-week washout and 1 week of the opposite treatment. Key inclusion criteria were age 18 to 70 years, body mass index 18.0 to 30.0 kg/m FINDINGS: Among the 24 total participants who were randomized to treatment and completed the twice daily dosing phase study, their mean age was 38.6 years (range, 20-62 years), 54% were women, and 83% had spastic CP. Adverse events were consistent with previous D-ER trials, most commonly headache (13% D-ER, 4% placebo), fatigue (13% D-ER, 0% placebo), insomnia (8% D-ER, 4% placebo), diarrhea (4% D-ER, 4% placebo), and nausea (4% D-ER, 4% placebo). The mixed model analysis of full crossover data identified no significant difference between D-ER and placebo in the primary functional analysis (the most pronounced deficit; P = 0.70) or in the secondary analyses (hand strength [P = 0.48], manual dexterity [P = 0.13], or walking speed [P = 0.42]). IMPLICATIONS: In this preliminary study of adults with CP, a BID dose of 10-mg D-ER was generally safe and well tolerated. The exploratory functional assessments for upper and lower sensorimotor deficits did not establish that the study population was markedly responsive to D-ER relative to placebo. These findings do not provide the proof-of-concept that would support further evaluation of D-ER as a potential intervention to improve function in adults with CP. ClinicalTrials.gov identifier: NCT01468350