PMID- 36268811 OWN - NLM STAT- MEDLINE DCOM- 20230208 LR - 20230419 IS - 1528-1167 (Electronic) IS - 0013-9580 (Print) IS - 0013-9580 (Linking) VI - 64 IP - 2 DP - 2023 Feb TI - A randomized phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato(R) alprazolam for rapid seizure termination. PG - 374-385 LID - 10.1111/epi.17441 [doi] AB - OBJECTIVE: Alprazolam administered via the Staccato(R) breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. METHODS: Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h. RESULTS: A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs. SIGNIFICANCE: Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting. CI - (c) 2022 Engage Therapeutics. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. FAU - French, Jacqueline AU - French J AUID- ORCID: 0000-0003-2242-8027 AD - New York University, Langone Health, New York, New York, USA. FAU - Biton, Victor AU - Biton V AD - Arkansas Epilepsy Program, Little Rock, Arkansas, USA. FAU - Dave, Hina AU - Dave H AD - University of Texas Southwestern Medical Center, Dallas, Texas, USA. FAU - Detyniecki, Kamil AU - Detyniecki K AD - University of Miami, Coral Gables, Florida, USA. FAU - Gelfand, Michael A AU - Gelfand MA AD - University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Gong, Hui AU - Gong H AD - Rancho Los Amigos National Rehabilitation Center, Downey, California, USA. FAU - Liow, Kore AU - Liow K AD - Hawaii Pacific Neuroscience, Honolulu, Hawaii, USA. FAU - O'Brien, Terence J AU - O'Brien TJ AD - Monash University and Alfred Hospital, Melbourne, Australia. FAU - Sadek, Ahmed AU - Sadek A AD - Research Institute of Orlando, LLC, Orlando, Florida, USA. FAU - DiVentura, Bree AU - DiVentura B AD - The Epilepsy Study Consortium, Woodbury, New Jersey, USA. FAU - Reich, Brittany AU - Reich B AD - Engage Therapeutics, Inc., Summit, New Jersey, USA. FAU - Isojarvi, Jouko AU - Isojarvi J AD - Engage Therapeutics, Inc., Summit, New Jersey, USA. LA - eng SI - ClinicalTrials.gov/NCT03478982 GR - Engage Therapeutics Inc./ PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20221207 PL - United States TA - Epilepsia JT - Epilepsia JID - 2983306R RN - YU55MQ3IZY (Alprazolam) RN - 0 (Anticonvulsants) SB - IM MH - Adult MH - Humans MH - *Alprazolam/therapeutic use MH - Anticonvulsants/adverse effects MH - Treatment Outcome MH - Seizures/drug therapy/chemically induced MH - *Epilepsy/drug therapy MH - Double-Blind Method PMC - PMC10107237 OTO - NOTNLM OT - acute treatment OT - alprazolam OT - clinical trial OT - deep lung delivery OT - epilepsy OT - rapid onset OT - seizure COIS- Staccato(R) is a registered trademark of Alexza Pharmaceuticals, Inc. and is used by UCB Pharma under license. Jacqueline French receives salary support from the Epilepsy Foundation and for consulting work and/or attending scientific advisory boards on behalf of The Epilepsy Study Consortium for Adamas, Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Baergic Bio, Biogen, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, BridgeBio Pharma Inc., Cavion, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Corlieve Therapeutics, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Inc., Engrail, Epalex, Epihunter, Epiminder, Equilibre BioPharmaceuticals, Fortress Biotech, Greenwich Biosciences, GW Pharmaceuticals, Janssen Pharmaceuticals, Knopp Biosciences, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuropace, NxGen Medicine Inc., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Pfizer, Praxis, PureTech LTY Inc., Redpin, Sage, SK Life Science, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Pharma, West Therapeutic Development, Xenon Pharmaceuticals, Xeris, Zogenix, and Zynerba; has received research support from the Epilepsy Study Consortium (funded by Andrews Foundation, Eisai, Engage Therapeutics, Inc., Lundbeck, Pfizer, SK Life Science, Sunovion, UCB Pharma, and Vogelstein Foundation), Epilepsy Study Consortium/Epilepsy Foundation (funded by UCB Pharma), GW Pharmaceuticals/Finding A Cure for Epilepsy and Seizures (FACES), and National Institute of Neurological Disorders and Stroke; is on the editorial board of Lancet Neurology and Neurology Today; is chief medical/innovation officer for the Epilepsy Foundation; and has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Arvelle Therapeutics, Inc., Biogen, Cerevel, Clinical Education Alliance, Engage Therapeutics, Inc., Lundbeck, NeuCyte, Inc., Otsuka Pharmaceutical Development, Sage, UCB Pharma, Xenon Pharmaceuticals, Inc., and Zogenix. Hina Dave served on the advisory board to Engage Therapeutics, Inc., but did not receive any consultation fees. Kamil Detyniecki has served as an advisory board member for Greenwich Pharma; and has received consultation fees from/served on advisory boards for Aquestive Therapeutics, Neurelis, and UCB Pharma. Michael A. Gelfand has received research funding from Aquestive Therapeutics, Cerevel, LivaNova, Otsuka, SK Pharma, UCB Pharma, and Xenon Pharmaceuticals, Inc. Terence J. O'Brien has received support from and/or has served as a paid consultant for Eisai, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke, Praxis Precision Medicines, Royal Melbourne Hospital Neuroscience Foundation, UCB Pharma, and Zynerba Pharmaceuticals. Ahmed Sadek has served as advisory board member for GW Pharmaceuticals and SK Life Science; speaker for Sunovion; and has received research support from Sunovion and UCB Pharma. Bree DiVentura is an employee of The Epilepsy Study Consortium. The Consortium consulted with Alexza Pharmaceuticals, Inc., Engage Therapeutics, Inc., and UCB Pharma and was paid for these services. Within the past year the Epilepsy Consortium has received funding for research support, meeting support, and services provided from the following companies: Alterity Therapeutics Limited, Amzell, Anavex, Aquestive Therapeutics, Arvelle Therapeutics, Inc., Autifony Therapeutics Limited, Biogen, BioMarin Pharmaceutical Inc., Bloom Science, BridgeBio Pharma Inc., Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Corlieve Therapeutics, Eisai Medical Research, Eliem Therapeutics, Encoded Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Equilibre BioPharmaceuticals, Greenwich Biosciences, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Knopp Biosciences, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Medtronic, Neumirna Therapeutics, Neurelis, Neurocrine, Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Praxis, Prevail Therapeutics, PureTech LYT Inc., Rafa Laboratories Ltd., SK Life Science, Stoke, Supernus, Takeda, UCB Pharma, Ultragenyx Pharmaceutical Inc., Ventus Therapeutics, Xenon Pharmaceuticals, and Zogenix. Brittany Reich and Jouko Isojarvi were salaried employees of Engage Therapeutics, Inc., and received stock or stock options from their employment at the time this study was conducted. The remaining authors have no conflicts of interest. 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. EDAT- 2022/10/22 06:00 MHDA- 2023/02/09 06:00 PMCR- 2023/04/17 CRDT- 2022/10/21 06:03 PHST- 2022/10/17 00:00 [revised] PHST- 2022/06/22 00:00 [received] PHST- 2022/10/19 00:00 [accepted] PHST- 2022/10/22 06:00 [pubmed] PHST- 2023/02/09 06:00 [medline] PHST- 2022/10/21 06:03 [entrez] PHST- 2023/04/17 00:00 [pmc-release] AID - EPI17441 [pii] AID - 10.1111/epi.17441 [doi] PST - ppublish SO - Epilepsia. 2023 Feb;64(2):374-385. doi: 10.1111/epi.17441. Epub 2022 Dec 7.