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Clinical Trial
. 2022 Apr;63(4):836-843.
doi: 10.1111/epi.17177. Epub 2022 Feb 2.

Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study

Michael R Sperling  1 , James W Wheless  2 , R Edward Hogan  3 , Dennis Dlugos  4 , Gregory D Cascino  5 , Kore Liow  6 , Adrian L Rabinowicz  7 , Enrique Carrazana  7   8 ; DIAZ 001.05 Study Group
Affiliations
Clinical Trial

Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study

Michael R Sperling et al. Epilepsia. 2022 Apr.

Abstract

Objective: An exploratory analysis from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures.

Methods: Seizures and doses were recorded in diaries.

Results: Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1-82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0-4 h, 152 (3.9%); 4-6 h, 72 (1.9%); 6-8 h, 39 (1.0%); 8-12 h, 55 (1.4%); 12-16 h, 42 (1.1%); 16-20 h, 42 (1.1%); 20-24 h, 83 (2.2%). Rates of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively).

Significance: Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)-approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours.

Keywords: acute repetitive seizures; diazepam; intranasal; rescue.

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Conflict of interest statement

Dr. Sperling has received compensation for speaking at continuing medical education (CME) programs from Medscape, Projects for Knowledge, International Medical Press, Eisai, and UCB Pharma. He is an advisor for scientific publications for Neurelis. He consults for Medtronic with payments to Thomas Jefferson University. He has received research support from Eisai Inc.; Medtronic; Neurelis, Inc.; SK Life Science; Takeda; Xenon; Cerevel; UCB Pharma; and Engage Pharmaceuticals. He has received royalties from Oxford University Press. Dr. Wheless has served as an advisor or consultant for CombiMatrix; Eisai Inc.; GW Pharmaceuticals; Lundbeck, Inc.; Neurelis, Inc.; NeuroPace, Inc.; Supernus Pharmaceuticals, Inc.; and Upsher‐Smith Laboratories, Inc. Dr. Wheless has served as a speaker or a member of a speakers bureau for Cyberonics, Inc.; Eisai Inc.; Lundbeck, Inc.; Mallinckrodt; Neurelis, Inc.; Supernus Pharmaceuticals, Inc.; and Upsher‐Smith Laboratories, Inc., and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; and INSYS. Dr. Hogan has received research support from UCB Pharmaceuticals, Neurelis, Inc; and Biogen Inc, and is an advisor for Neurelis, Inc. Dr. Dlugos receives salary support from The Epilepsy Study Consortium. His institution receives research support for protocol development or studies from Zogenix; Greenwich Biosciences; Neurelis, Inc.; Aquestive; Bio‐Pharm; Stoke Therapeutics; SK Life Science; and Encoded Therapeutics. He received travel expenses for protocol development or investigator meetings from Marinus, Ovid/Takeda, and Zogenix. Dr. Cascino has nothing to disclose. Dr. Liow has received research support from Intra‐Cellular Therapies, SK Life Science, Genentech, Biotie Therapies, Monosol, Aqestive Therapeutics, Engage Therapeutics, Xenon, Lundbeck, Biogen, Eli Lilly, Pfizer, Novartis, Sunovion, Acorda, Eisai, UCB Pharma, LivaNova, Axsome, and Acadia. Dr. Rabinowicz is an employee and has received stock options from Neurelis, Inc. Dr. Carrazana is an employee of and has received stock and stock options from Neurelis, Inc. 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.

Figures

FIGURE 1
FIGURE 1
Frequency of second dose use of diazepam nasal spray in the safety population (N = 163 patients)
FIGURE 2
FIGURE 2
Percentage of an individual patient's total seizure clusters treated with a second dose of diazepam nasal spray (N = 79 patients)
FIGURE 3
FIGURE 3
Time to second dose when used
See this image and copyright information in PMC

References

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