TY - JOUR
T1 - Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy
T2 - Interim results from a phase 3, open-label, repeat-dose safety study
AU - DIAZ.001.05 Study Group
AU - Cascino, Gregory D.
AU - Tarquinio, Daniel
AU - Wheless, James W.
AU - Hogan, R. Edward
AU - Sperling, Michael R.
AU - Liow, Kore
AU - Desai, Jay
AU - Davis, Charles
AU - Rabinowicz, Adrian L.
AU - Carrazana, Enrique
N1 - Funding Information:
Dr. Cascino has nothing to disclose. Dr. Tarquinio has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis; Marinus; and Neurelis, Inc. 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.; Upsher-Smith Laboratories, Inc., and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; Insys Therapeutics, Inc.; Lundbeck, Inc.; Mallinckrodt; Neurelis, Inc.; NeuroPace, Inc.; Upsher-Smith Laboratories, Inc.; and Zogenix, Inc. Dr. Hogan has received research support from UCB Pharmaceuticals, Neurelis, Inc; and Biogen, Inc., and is an advisor for Neurelis, Inc. Dr. Sperling has received personal compensation for speaking from Neurology Live and Eisai, Inc., is an advisor for Neurelis, Inc., and consulting with payments to Thomas Jefferson University from Medtronic. Dr Sperling has received research support from Eisai, Inc.; Medtronic; Neurelis, Inc.; SK Life Science; Takeda; Sunovion; UCB Pharmaceuticals; Xenon; and Engage Pharmaceuticals. Dr. Liow has received research support from Intracellular Therapies, SK Life Science, Genentech, Biotie Therapies, Monosol, Aquestive Therapeutics, Engage Therapeutics, Xenon, Lundbeck, Biogen, Inc., Eli Lilly, Pfizer, Novartis, Sunovion, Acorda, Eisai, Inc., UCB, Livanova, Axsome, and Acadia. Dr. Desai has received research funding from the Epilepsy Foundation of Greater Los Angeles; Neurelis, Inc.; Novartis; Ovid; Aquestive; and UCB Pharmaceuticals. Dr. Davis is a consultant to Neurelis, Inc. Dr. Rabinowicz is an employee of and has received stock options from Neurelis, Inc.
Funding Information:
Editorial support was provided by Miranda Tradewell, PhD, for The Curry Rockefeller Group, LLC (Tarrytown, NY), and was funded by Neurelis, Inc (San Diego, CA).
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/7
Y1 - 2021/7
N2 - 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 < 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.
AB - 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 < 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.
KW - Benzodiazepines
KW - Diazepam nasal spray
KW - Rescue therapy
KW - Seizure clusters
KW - Tolerance
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U2 - 10.1016/j.yebeh.2021.107983
DO - 10.1016/j.yebeh.2021.107983
M3 - Article
C2 - 33957437
AN - SCOPUS:85105057943
VL - 120
JO - Epilepsy and Behavior
JF - Epilepsy and Behavior
SN - 1525-5050
M1 - 107983
ER -