Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy

James W Wheless, Ian Miller, R Edward Hogan, Dennis Dlugos, Victor Biton, Gregory D Cascino, Michael R Sperling, Kore Liow, Blanca Vazquez, Eric B Segal, Daniel Tarquinio, Weldon Mauney, Jay Desai, Adrian L Rabinowicz, Enrique Carrazana, DIAZ.001.05 Study Group, James W Wheless, Ian Miller, R Edward Hogan, Dennis Dlugos, Victor Biton, Gregory D Cascino, Michael R Sperling, Kore Liow, Blanca Vazquez, Eric B Segal, Daniel Tarquinio, Weldon Mauney, Jay Desai, Adrian L Rabinowicz, Enrique Carrazana, DIAZ.001.05 Study Group

Abstract

Objective: A Phase 3 open-label safety study (NCT02721069) evaluated long-term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters.

Methods: Patients were 6-65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment-emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded.

Results: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis.

Significance: In this large open-label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters.

Keywords: acute repetitive seizure; diazepam; intranasal; rescue; stereotypic episodes of frequent seizure activity.

Conflict of interest statement

J.W.W. has served as an advisor or consultant for CombiMatrix, Eisai, GW Pharmaceuticals, Lundbeck, Neurelis, NeuroPace, Supernus Pharmaceuticals, and Upsher‐Smith Laboratories; has served as a speaker or a member of a speakers bureau for Cyberonics, Eisai, Lundbeck, Mallinckrodt, Neurelis, Supernus Pharmaceuticals, and Upsher‐Smith Laboratories; and has received grants for clinical research from Acorda Therapeutics, GW Pharmaceuticals, Insys Therapeutics, Lundbeck, Mallinckrodt, Neurelis, NeuroPace, Upsher‐Smith Laboratories, and Zogenix. I.M. is an employee of Marinus Pharmaceuticals and has served as a consultant/advisor and/or speaker for GW Pharmaceuticals, Insys Therapeutics, Neurelis, NeuroPace, and Visualase and as a study investigator for GW Pharmaceuticals. R.E.H. has received research support from UCB Pharmaceuticals, Neurelis, and Biogen, and is an advisor for Neurelis. D.D. receives salary support from the NIH, Commonwealth of Pennsylvania Department of Health, Pediatric Epilepsy Research Foundation, and Epilepsy Study Consortium; is an investigator on research grants awarded to CHOP from Zogenix, Greenwich Biosciences, UCB, Brain Sentinel, Neurelis, Q‐State, USL, Aquestive, Bio‐Pharm, Insys, SK Life Science, and Encoded Therapeutics; has received travel expenses for protocol development conferences or investigator meetings from Marinus, Ovid/Takeda, Ultragenyx, USL, Pfizer, and Zogenix; and has received honoraria and/or travel support for continuing medical education and other educational programs from Wake Forest University School of Medicine, American Epilepsy Society, American Academy of Neurology, Epilepsy Foundation of America, Epilepsy Foundation of North Carolina, Medscape, Miller Medical Communications, Ecuador Neurology Project, Ministry of Health of the United Arab Emirates, and Seoul National University. M.R.S. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Medtronic and is an advisor for Neurelis and has received research support from Eisai, Medtronic, Neurelis, Pfizer, SK Life Science, Takeda, Sunovion, UCB Pharma, and Upsher‐Smith. K.L. has received research support from Intracellular Therapies, SK Life Science, Genentech, Biotie Therapies, Monosol, Aquestive Therapeutics, Engage Therapeutics, Xenon, Lundbeck, Biogen, Eli Lilly, Pfizer, Novartis, Sunovion, Acorda, Eisai, UCB, Livanova, Axsome, and Acadia. B.V. is an advisor for Neurelis. E.B.S. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Lundbeck, Nutricia, Novartis, Greenwich, Epitel, Encoded Therapeutics, and Qbiomed and is an advisor for Neurelis. D.T. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Marinus, and Neurelis. J.D. has received research funding from the Epilepsy Foundation of Greater Los Angeles, Neurelis, Novartis, Ovid, Aquestive, and UCB. A.L.R. is an employee of and has received stock options from Neurelis. E.C. is an employee of and has received stock and stock options from Neurelis. None of the other authors has any conflict of interest to disclose. 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.

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Patients remaining on study over time

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