Faster Initiation of Diazepam Nasal Spray Associated With More Rapid Seizure Termination

Danielle Becker, MD, MS, FAES

A subgroup analysis of a phase 3 safety study (NCT0272109) showed that shorter time to treatment with diazepam nasal spray (Valtoco; Neurelis), preferably within 5 min of a seizure, was associated with shorter time to seizure cluster termination. Investigators concluded that these findings warrant further exploration of their clinical implications and generalizability.¹

The data, presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, showed that for seizures treated within 5 minutes, median times to dose seizure termination were 2 and 3 minutes, respectively, for adults and pediatric patients. In comparison, for 727 seizures treated within 5-15 minutes, time from dosing to termination were 10 and 5 minutes, while for 329 seizures treated after 15 minutes, times from dosing to termination were 20 and 8 minutes.

Led by Danielle Becker, MD, MS, FAES, division director of epilepsy and associate professor of neurology at The Ohio State University Wexner Medical Center, the trial included 3225 observations of seizures from 163 patients. Observations recording seizure duration greater than 24 hours, negative duration, and invalid dose date/time values were excluded from the analysis. Overall, the number of observations were similar for adults (n = 1567) and pediatric patients (n = 1658).

In a subgroup of 61 adult and pediatric patients with more than 20 observations, combined results showed that those treated with diazepam within 5 minutes had time from dosing to termination of 3 minutes. In comparison, those treated past the 5-minute mark experienced time from dosing to termination of 11 minutes. The study authors also concluded that the safety of the therapy was similar to diazepam rectal gel, another form of the antiseizure medication.

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In a previous post-hoc analysis of this phase 3 study, data showed that treatment with diazepam results in statistically significant change in SEIzure interVAL (SEIVAL), or the time between seizure clusters, that was independent of age or changes in concomitant ASMs. SEIVAL was evaluated across 4 consecutive 90-day periods, totaling 360 days, with paired t tests to assess statistical significance. In total, 76 patients had data in all 4 periods, representing a consistent cohort.²

In the general population, findings showed that from period 1 to 4, treated patients had mean SEIVAL increase from 14.8 to 35.8 days. In the consistent cohort, mean SEIVAL increased from 13.9 to 26.8 days (P ≤.001). Among a subgroup of pediatric participants aged 6-17 years old (n = 32), mean SEIVAL increased from 13.0 to 25.9 days (P = .02). In adults (n = 44), mean SEIVAL increased from 14.6 to 27.5 days (P = .01). Notably, treatment with diazepam nasal spray resulted in increased mean SEIVAL among patients with (n = 56) changes in concomitant ASM therapy, going from 13.9 to 25.8 days, and those without (n = 20), increasing from 14.1 to 29.6 days.

The original phase 3 study, an open-label trial, included a 12-month treatment period, with study visits at day 30 and every 60 days thereafter, after which patients could elect to continue treatment. Safety findings showed 1 death because of sudden unexplained death in epilepsy and 1 withdrawal of the drug owing to a treatment-related adverse event, both of which were considered unlikely to be related to diazepam. Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes.³

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REFERENCES
1. Becker D, Jarrar R, Stern J, Rabinowicz A, Carrazana E. Shorter time to treatment with diazepam nasal spray is associated with faster seizure termination: a subpopulation analysis. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. ABSTRACT 005291
2. Misra SN, Sperling MR, Rao VR, et al. Significant improvements in SEIzure InterVAL (time between seizure clusters) across time: post hoc analysis of a long-term, open-label study of diazepam nasal spray. Presented at: 2023 International Epilepsy Congress; September 2-6; Dublin, Ireland. Abstract 655
3. Wheless JW, Miller I, Hogan RE, et al. Final results from a phase 3, long-term, open-label, repeast-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy. Epilepsia. 2021;62(10):2485-2495. doi:10.1111/