Increased interval between seizure clusters across time in pediatric patients treated with the immediate‐use seizure medication diazepam nasal spray

Abstract

Objective

Seizure clusters, intermittent increases in seizure activity that differ from a patient's usual seizure pattern, may occur despite treatment with a daily anti‐seizure medication. Benzodiazepine‐containing immediate‐use seizure medications (ISMs; also called rescue therapies) are the cornerstone of treatment for seizure clusters. Diazepam nasal spray is approved by the U.S. Food and Drug Administration to treat seizure clusters in patients with epilepsy ≥2 years of age. A prior long‐term safety study of diazepam nasal spray showed an increased inter‐seizure cluster interval (SEIzure interVAL [SEIVAL]) in days across a year in patients 6 to 65 years of age. The current analysis focused on changes in SEIVAL over time in a separate study in children with epilepsy 2 to 5 years of age.

Methods

Patients with epilepsy 2 to 5 years of age were enrolled in an open‐label, Phase 1/2a trial of diazepam nasal spray that included a single‐dose pharmacokinetics period, 180‐day safety period, and optional extension period. Doses of 5, 10, or 15 mg were administered based on weight (0.5 mg/kg). A post hoc analysis evaluated SEIVAL for consecutive 90‐day periods overall and in a consistent cohort of patients with persistent use and SEIVALs in each period.

Results

Among enrolled patients (n = 36), 22 (61.1%) had ≥1 SEIVAL, with a total of 315 SEIVALs recorded. Mean SEIVAL (±SD) doubled from 25.2 (±21.3) days in Period 1 (n = 20) to 51.9 (±72.4) days in Period 3 (n = 8). In the consistent cohort (n = 7), mean SEIVAL increased from 22.1 (±12.7) days in Period 1 to 27.7 (±25.4) days in Period 3.

Significance

These results corroborate those of the earlier post hoc analysis of data from patients 6 to 65 years of age who received diazepam nasal spray for seizure clusters. These findings suggest a beneficial long‐term treatment effect of diazepam nasal spray beyond acute use as an ISM.

Key points.

• This post hoc analysis included data from a pharmacokinetics and safety study of diazepam nasal spray in patients 2 to 5 years of age.

• SEIzure interVAL (SEIVAL) was used to assess changes in the time in days between treated seizure episodes over time using 90‐day periods.

• The mean SEIVAL increased across three periods overall and in a consistent cohort with persistent use and SEIVALS in all three periods.

• These findings support a previously identified long‐term effect observed in the long‐term safety study of older patients treated with diazepam nasal spray.

1. INTRODUCTION

Seizure clusters have been described as intermittent increases in seizure activity during a specific period of time (e.g., 24 h) that differ from a patient's usual seizure pattern. ¹ , ² Both adult and pediatric patients with epilepsy may have these episodes, despite daily treatment with anti‐seizure medications. ² , ³

Prompt recognition and effective treatment of seizure clusters is essential for reducing the risk of negative outcomes, including progression to status epilepticus and emergency room visits. ³ , ⁴ Benzodiazepine‐containing immediate‐use seizure medications (ISMs; also called rescue therapies) are the cornerstone of treatment for seizure clusters. ⁴ , ⁵ Rapid treatment with an ISM has been associated with faster termination of seizure clusters. ⁶ In the United States, diazepam rectal gel and diazepam nasal spray are approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy ≥2 years of age, and midazolam nasal spray is approved in patients ≥12 years of age. ⁷ , ⁸ , ⁹

Historically, the effectiveness of ISMs has been evaluated based on short‐term measures. These include termination of a treated seizure cluster and use of second doses to treat a seizure cluster. ¹⁰ , ¹¹ , ¹² There has been little investigation into potential longer‐term therapeutic or disease‐modifying effects. ¹³

Recently, the novel inter‐seizure cluster interval (SEIzure interVAL [SEIVAL]) metric has been used for observing changes in the time in days between treated seizure clusters, as it can be assessed over longer periods of time. ¹³ In a post hoc analysis of data from the long‐term safety study of the ISM diazepam nasal spray (treatment period, 1 year), which enrolled patients 6 to 65 years of age (N = 163), ¹² mean SEIVAL was assessed within 90‐day periods, with the goal of including a substantial number of patients with a SEIVAL in each equal, adjacent period. ¹³ Findings from this analysis showed that treatment with diazepam nasal spray was associated with significant and substantial increases in mean SEIVAL (indicating a reduction in treated seizure cluster frequency) over 1 year, including a doubling of mean SEIVAL between the first 90‐day period and the fourth period (Days 271–360) in a consistent cohort of patients with SEIVALs in each of the first four periods. ¹³

The present analysis examines SEIVAL across time in children with epilepsy 2 to 5 years of age who participated in a clinical trial evaluating diazepam nasal spray as an ISM in this age group. ¹⁴ The objective of this post hoc analysis was to determine whether there was a similar pattern of increase in SEIVAL in this age group as that observed in older patients treated with diazepam nasal spray.

2. MATERIALS AND METHODS

Patients with epilepsy 2 to 5 years of age were enrolled in an open‐label, Phase 1/2a trial (NCT05076838) of diazepam nasal spray that included a single‐dose pharmacokinetics (PK) period, a 180‐day safety period, and an optional extension period. ¹⁴ The main objectives of the study were to evaluate the PK and safety of diazepam nasal spray in this population of young children. ¹⁴

2.1. Patients

The study enrolled male and female children 2 to 5 years of age with a clinical diagnosis of epilepsy. ¹⁴ Patients had either partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness, for which rescue medications had been used ≥1 time in the past 3 months or, in the investigator's opinion, which may have needed an intervention with a benzodiazepine for seizure control 1 to 2 times every 3 months on average. No restrictions were made on use of other rescue medications or concomitant use of other benzodiazepines. History of status epilepticus or seasonal allergies was permitted. Key exclusion criteria were body weight <6 kg or >33 kg, ongoing intracranial electroencephalography monitoring, and in the investigator's opinion, clinically significant medical history or abnormal findings <30 days prior to or during screening that would jeopardize the safety of the patient or impact the validity of the study results. ¹⁴

2.2. Dosing

Diazepam nasal spray dosing was weight‐based (0.5 mg/kg), using the guidelines for diazepam rectal gel as approved by the U.S. Food and Drug Administration, and rounded to the nearest of 5, 10, or 15 mg. ¹⁴ A single dose of diazepam nasal spray was administered to the patient at the study site during the PK period. During the open‐label safety and extension periods, caregivers administered diazepam nasal spray on an as‐needed basis in the community setting. Second doses could be administered if needed. The investigator could increase or decrease a patient's dosage for efficacy or safety reasons, based on their clinical judgment, if there were no safety concerns associated with such a change. ¹⁴

Any change to any patient's concomitant anti‐seizure medication during the study was at the discretion of the study investigator. No restrictions on such changes were provided in the protocol.

2.3. SEIVAL analysis

The post hoc SEIVAL analysis population comprised all patients in the study with ≥1 calculable SEIVAL (i.e., 2 treated seizure episodes within a 90‐day period). ¹³ Data on the timing of administration of diazepam nasal spray and the timing of seizure onset and resolution were collected from the daily electronic diaries provided to the patients in the study. ¹⁴ SEIVAL was analyzed for consecutive 90‐day periods (e.g., Period 1 [Days 1–90], Period 2 [Days 91–180], Period 3 [Days 181–270]). ¹³

The starting date for period assignments was the date of the patient's first dose during the 180‐day safety period. The interval between a prior seizure episode and the subsequent seizure episode was computed using date and time. SEIVAL duration in days was calculated with following formula: (date of seizure episode – date of prior seizure episode) + 1 day. SEIVALs were assigned to a specific 90‐day period based on interval closure date; for example, an interval straddling Period 2 and Period 3 was assigned to Period 3.

Mean SEIVAL duration for each period was calculated for the overall cohort of patients with ≥1 SEIVAL in Period 1 and another period. In addition, a consistent cohort analysis was performed that included only participants with ≥1 SEIVAL in each of the first three 90‐day periods, to account for potential confounding introduced by the assessment of a variable cohort over time. ¹³ This addresses the possibility that patients might discontinue the study if they did not feel they benefited from administration of the study medication. ¹³ Data were described using summary statistics only (mean and SD).

2.4. Safety

Patients returned to the study site on Days 30, 90, and 180 for safety evaluations, including recording treatment‐emergent adverse events (TEAEs). ¹⁴ Phone calls were conducted on Days 60, 120, and 150 to determine whether any TEAEs had occurred and to follow up on any ongoing TEAEs. Serious TEAEs were reported when they occurred. Patients who entered the optional extension period had safety visits every 90 days. ¹⁴

3. RESULTS

3.1. Overall study

Of the 36 patients 2 to 5 years of age enrolled in the study and included in the safety population, 35 (97.2%) entered and 31 (86.1%) completed the 180‐day safety period, and 27 (75.0%) entered and completed the optional extension period. Enrolled patients had a mean (±SD) age of 3.9 (±1.0) years (range, 2.0–5.8 years); 19 patients (52.8%) were 2 to 3 years of age, and 17 patients (47.2%) were 4 to 5 years of age. Mean (±SD) body weight was 17.5 (±4.9) kg. The main findings of the PK and open‐label safety period were published previously. ¹⁴

3.2. SEIVAL analysis

Twenty‐two patients (61.1%) had ≥1 SEIVAL reported, with a total of 315 SEIVALs reported for all patients during the study; 14 patients (38.9%) who did not have SEIVALs were excluded from this analysis (Figure 1). For the 315 SEIVALs, mean (±SD) SEIVAL duration was 25.9 (±56.4) days. In the overall cohort analysis of SEIVAL over time (Figure 2), the mean (±SD) SEIVAL duration more than doubled from 25.2 (±21.3) days in Period 1 (n = 20) to 51.9 (±72.4) days in Period 3 (n = 8). For Periods 1 to 6, ≥5 patients in each period had ≥1 SEIVAL in Period 1 and another period; fewer patients had data in later periods (Figure 2).

FIGURE 1.

Patient disposition. SEIVAL, inter‐seizure cluster interval.

FIGURE 2.

Mean SEIVAL duration for the overall cohort (n = 22). SEIVAL, inter‐seizure cluster interval.

Seven patients with SEIVALS in each of Periods 1, 2, and 3 were included in the consistent cohort; 15 patients who did not have ≥1 SEIVAL in all three periods were excluded. The mean (±SD) SEIVAL duration in the consistent cohort increased from 22.1 (±12.7) days in Period 1 to 27.7 (±25.4) days in Period 3 (Figure 3).

FIGURE 3.

Mean SEIVAL duration for the consistent cohort (n = 7). SEIVAL, inter‐seizure cluster interval.

3.3. Safety

In the 180‐day open‐label safety period of the study, 24 patients (66.7%) experienced a TEAE, 10 patients (27.8%) had a serious TEAE (none of which were related to treatment), and 7 patients (19.4%) had a treatment‐related TEAE (Table 1). ¹⁴ Serious TEAEs in ≥ 2 patients were seizure in 3 patients (8.3%) and epilepsy in 2 patients (5.6%); serious TEAEs of interest, status epilepticus and respiratory depression, occurred in 1 patient each (2.8%). Treatment‐related TEAEs occurred in one patient each. The most common TEAEs (>20%) were rhinorrhea (25.0%) and pyrexia (22.2%). During the optional extension period, 24 patients (88.9%) experienced a TEAE, and 7 patients (25.9%) had a serious TEAE (none related to treatment). The most common TEAEs (>15%) were rhinorrhea (22.2%) and pyrexia (18.5%). Serious TEAEs in ≥2 patients were status epilepticus in 4 patients (14.8%) and pneumonia and urinary tract infection in 2 patients each (7.4%); serious TEAEs of interest, acute respiratory failure and respiratory failure, occurred in 1 patient each (3.7%). One patient (3.7%) had a treatment‐related TEAE (vomiting). No TEAEs resulted in death or discontinuation at any time during the study.

TABLE 1.

Treatment‐emergent adverse events.

Type	180‐day open‐label safety period (N = 36), n (%)	Optional extension period (n = 27), n (%)
Any TEAE	24 (66.7)	24 (88.9)
Related to treatment	7 (19.4)	1 (3.7)
Serious TEAE	10 (27.8)	7 (25.9)
Related to treatment	0	0
TEAEs leading to study discontinuation	0	0
TEAEs leading to death	0	0
Most common TEAEs >10% in either period)
Rhinorrhea	9 (25.0)	6 (22.2)
Pyrexia	8 (22.2)	5 (18.5)
Nasal mucosal disorder	4 (11.1)	4 (14.8)
Nasopharyngitis	4 (11.1)	2 (7.4)
Seizure	4 (11.1)	2 (7.4)
Upper respiratory tract infection	3 (8.3)	4 (14.8)
Influenza	2 (5.6)	4 (14.8)
Status epilepticus	1 (2.8)	4 (14.8)
Diarrhea	1 (2.8)	3 (11.1)
Pharyngitis streptococcal	1 (2.8)	3 (11.1)
Pneumonia	1 (2.8)	3 (11.1)
Viral infection	3 (8.3)	3 (11.1)
Vomiting	2 (5.6)	3 (11.1)
Treatment‐related TEAEs
Administrative site pain	1 (2.8)	0
Blepharitis	1 (2.8)	0
Nasal edema	1 (2.8)	0
Nasal mucosal disorder	1 (2.8)	0
Pneumonia aspiration	1 (2.8)	0
Rhinorrhea	1 (2.8)	0
Somnolence	1 (2.8)	0
Vomiting	1 (2.8)	1 (3.7) a

Abbreviation: TEAE, treatment‐emergent adverse event.

^a The same patient had this treatment‐related TEAE in the safety period and the extension.

4. DISCUSSION

This Phase 1/2a, open‐label PK and safety study evaluating the ISM diazepam nasal spray for seizure episodes in patients 2 to 5 years of age demonstrated the appropriateness, favorable safety profile, and effectiveness of a 0.5 mg/kg dose in this age group. ¹⁴ Administration with the same unit dose device system as approved for use for older patients was shown to be appropriate for the nasal opening of these very young patients, with a low administration error rate for nonmedical caregivers in the community setting (0.7%). ¹⁴ Nasal administration can address the limitations of diazepam rectal gel, with fewer time‐consuming steps to the process. ³

In this post hoc analysis, SEIVAL increased from baseline in patients 2 to 5 years of age, with a pattern generally similar to that observed in older patients (6–65 years) in the Phase 3 study of diazepam nasal spray. In that study, SEIVAL increased in the overall cohort (increase from 14.8 days mean SEIVAL at Period 1 to 26.9 days at Period 3) and the consistent cohort with persistent use (increase from 13.9 days in Period 1 to 21.7 days at Period 3, p < 0.01). ¹³ In an analysis of data from pediatric patients (n = 32 patients 6–17 years of age) in the Phase 3 safety study, mean SEIVAL increases were observed from 13.0 days in the Period 1 to 17.7 days at Period 3. In the subgroup of pediatric patients with developmental and epileptic encephalopathies (DEEs) in that study (n = 28), SEIVAL increased from 11.7 days in Period 1 to 17.1 days in Period 3. ¹⁵

The increase in SEIVAL suggests decreased use of diazepam nasal spray and reduced likeliness of dependence on this benzodiazepine therapy, as well as the possibility of fewer seizure emergencies over time. ¹³ Thus, consistent, appropriate persistence/adherence to therapy administration may be beneficial. This also supports the lack of tolerance previously shown with diazepam nasal spray. ¹⁶

The explanation for the increase in SEIVAL over time is unclear; hypotheses for this observation in older patients have been explored. ¹³ These hypotheses include disease‐modifying biological factors, behavioral reasons, and regression to the mean. Potential for disease‐modifying effects of intermittent ISMs leading to reduction in seizures could be of considerable value for patients with epilepsy, especially if such effects could begin in childhood and might reduce the burden on activities of daily living and quality of life associated with seizures in the lives of patients and caregivers. ² , ¹³ Disease modification with treatment has been shown with other neurological disorders, such as multiple sclerosis, ¹⁷ including therapy use during an acute episode, which may improve long‐term outcomes. ¹⁸ Both symptomatic and disease‐modifying effects have been seen for a single therapy. ¹⁸ Investigation regarding disease modification in epilepsy is preliminary, with no mechanism yet identified. ¹³ Disease‐modifying effects of intermittent therapy have been examined using a preclinical rescue therapy paradigm of repeat dosing diazepam in rats that mimics drug concentration and accumulation in humans ¹⁹ , ²⁰ and a post–status epilepticus rat model that demonstrated increased time between seizures in a cluster and improvement over time in seizure severity and proportion of seizures in a cluster. ²¹

Behavioral reasons for increased SEIVAL may include better recognition of when best to use treatment with repeated use over time and a reduction in the perceived need to use the therapy. ¹³ Regression to the mean suggests that patients with a higher frequency of seizures seek medical attention and that there is a natural tendency for the frequency to lessen with time. Such effects in epilepsy usually taper off in 3 to 6 months, ²² and the SEIVAL effect has been shown to be consistent for a much longer time period.

Limitations of this post hoc analysis include the unknown natural history of SEIVAL over time and the lack of an untreated comparison group, which was not available from the study. In addition, only 90‐day periods were examined here; however, further analysis into shorter periods (e.g., 70 days) is being pursued. In addition, the numbers of patients in both the overall and specifically the consistent cohort were small, due to the challenges inherent in enrolling very young patients in a clinical trial. ²³ Possible effect of changes to concomitant medications during the study was not performed for this small population; however, such changes were not shown to be a factor in the previous SEIVAL analysis in a larger group of patients 6–65 years of age in the long‐term safety study of diazepam nasal spray. ¹³ That analysis found no between‐group difference in SEIVAL for subgroups with and without changes to concomitant medications. ¹³ In the present analysis, although there is the potential for self‐selection bias for patients who continued into the optional extension with data in Period 3, such an effect is not reflected in the consistent cohort, which controlled for a variable population over time, or findings from the previous analysis in older patients in the safety population showed increases over a 360‐day period. ¹³ In addition, changes in medication adherence were not measured in this study and could be an area for future examination in association with SEIVAL.

5. CONCLUSIONS

In an open‐label study of the ISM diazepam nasal spray for the as‐needed treatment of seizure episodes in children 2 to 5 years of age, the mean time between seizure episodes increased as the treatment period progressed. This finding was supported when the analysis was repeated in a small subset of patients with seizure episodes in each the first three analysis periods (i.e., a consistent cohort). These results corroborate those of an earlier, similar post hoc analysis of a separate, larger dataset in patients 6 to 65 years of age who received diazepam nasal spray for seizure clusters. ¹³

These findings suggest a beneficial long‐term treatment effect of with appropriate adherence to diazepam nasal spray as an ISM. Additional studies are warranted to explore and elucidate the mechanism(s) that underpin these important observations, including exploration of other timeframes.

AUTHOR CONTRIBUTIONS

All authors provided substantial contributions to conception and design, drafting, and revising the manuscript critically for important intellectual content, and all authors gave final approval of the version to be submitted.

FUNDING INFORMATION

This study was funded by Neurelis, Inc. (San Diego, CA).

CONFLICT OF INTEREST STATEMENT

JWW has served as an advisor or consultant for UCB, Jazz Pharmaceuticals, Neurelis, Inc., Upsher‐Smith Laboratories, Inc., Nobelpharma, Stoke, Praxis, and Azurity. He has served as a speaker or a member of a speakers' bureau for Cyberonics, Inc., Neurelis, Inc., Jazz, and SKLSI, and has received grants for clinical research from Jazz Pharmaceuticals, Neurelis, Inc., NeuroPace, Inc., UCB, Praxis, Stoke, LivaNova, and Azurity. ES has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Encoded Therapeutics, Epitel, Greenwich, Lundbeck, Novartis, Nutricia, and Qbiomed, and is an advisor for Neurelis, Inc. JMP has served on advisory boards and as a consultant for Neurelis, Inc., Acadia Pharmaceuticals, Clouds of Care, UCB Pharma, and Jazz Pharmaceuticals. SMW has served as an advisor or consultant for Assertio. He has served as a speaker or a member of a speakers' bureau for Monteris, LivaNova, UCB, and Marinus. He has received grants or contracts from Biohaven, Jazz, UCB, Longboard, and Takeda; research support from Neurelis, Inc.; and royalties or licenses from Jazz. GB has nothing to disclose. CD is a consultant to Neurelis, Inc. LYN is an employee of and has received stock options from Neurelis, Inc. EC is an employee of and has received stock and stock options from Neurelis, Inc. ALR is an employee of and has received stock options from Neurelis, Inc.

ETHICS STATEMENT

The original study protocol, informed consent form, and other relevant study documentation were approved by ethics committees or institutional review boards at each site before study initiation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

CLINICAL TRIAL REGISTRATION

Pharmacokinetics Study of Valtoco® in Pediatric Subjects With Epilepsy, NCT05076838.

PATIENT CONSENT STATEMENT

A properly written and executed informed consent form, in compliance with the Declaration of Helsinki, Good Clinical Practices according to the International Conference on Harmonization guidelines, US Code of Federal Regulations (CFR) for Protection of Human Subjects (21 CFR 50.25, CFR 50.27, and CFR Part 56, Subpart A), and other applicable local regulations, was obtained for each subject prior to entering the subject into the clinical study.

DATA AVAILABILITY STATEMENT

All relevant data are presented in the article.