Psychosocial outcomes of repeated treatment of seizure clusters with midazolam nasal spray: Results of a phase 3, open-label extension trial

Abstract

Objective: To evaluate treatment satisfaction, level of anxiety, confidence about traveling with midazolam nasal spray (MDZ-NS), and health-related quality of life in patients with seizure clusters and their caregivers after repeated, intermittent use of MDZ-NS in the outpatient setting.

Methods: We analyzed the psychosocial outcome data from a phase 3, open-label extension trial (ARTEMIS-2; P261-402; NCT01529034) in patients 12 years of age and older with seizure clusters on a stable regimen of antiseizure medications. Caregivers administered MDZ-NS 5 mg when patients experienced a seizure cluster. A second dose could be given if seizures did not terminate within 10 min or recurred from 10 min to 6 h. Treatment Satisfaction Questionnaire for Medication (TSQM), the Intranasal Therapy Impact Questionnaire (ITIQ), and the Short Form-12 Health Survey version 2 (SF-12v2) were self-administered by patients and/or caregivers at prespecified visits.

Results: Of the one hundred and seventy-five patients enrolled in ARTEMIS-2, 161 (92.0%) received ≥ 1 dose of MDZ-NS and had a post-treatment seizure-related assessment and were included in the Efficacy Evaluable Set in this analysis, with a total of 1,998 treated seizure clusters over a median duration of 16.8 months. All TSQM scales showed improvement from the baseline of the double-blind ARTEMIS-1 trial (NCT01390220) to the last visit in ARTEMIS-2, indicating greater satisfaction with MDZ-NS across all domains, with a mean change from baseline of 8.8, 6.1, 4.3, and 6.2 for effectiveness (n = 135), side effects (n = 139), convenience (n = 139), and global satisfaction (n = 138), respectively. Change from baseline in TSQM scores generally increased with repeated MDZ-NS use. In both patients and caregivers, anxiety generally lessened with repeated MDZ-NS use, with a mean improvement in ITIQ scores in patients' anxiety since receiving MDZ-NS from 2.5 (n = 138) to 3.5 (n = 145) from visit 1 to the last visit (and from 2.6 [n = 156] to 3.6 [n = 160] for caregivers), respectively. From visit 1 (screening and enrollment in ARTEMIS-2) to visit 10 (after 16 seizure cluster episodes treated with MDZ-NS), the proportions of patients and caregivers who answered "strongly agree" or "agree" for confidence about traveling with an intranasal spray remained ≥ 79% and generally increased over repeated MDZ-NS use. Small positive mean changes in SF-12v2 scores from baseline to the last visit were observed in both patients and caregivers, respectively, for the domains of physical functioning (0.9, 1.1), role-physical (2.4, 0.3), bodily pain (1.7, 0.3), general health (0.6, 1.2), and role-emotional (2.1, 0.3), and in the physical health component (1.6, 1.0).

Conclusion: Patients and caregivers perceived MDZ-NS favorably, with improvement from baseline on perceived effectiveness, side effects, convenience, and global satisfaction in the TSQM. This is supported by progressively lower anxiety and higher confidence levels about traveling with MDZ-NS over repeated intermittent use in the ITIQ. The positive mean changes observed in SF-12v2 scores from baseline to the last visit were small in magnitude. Limitations of this exploratory analysis include the open-label trial design and that these questionnaires have not been directly validated in epilepsy to identify clinically important changes; however, this does not mean these findings are not clinically meaningful. Overall, MDZ-NS is a socially acceptable drug device for outpatient treatment of seizure clusters that has the potential to improve quality of life and overall independence.

Keywords: Epilepsy; Midazolam nasal spray; Patient-reported outcome; Psychosocial outcome; Rescue medication; Seizure cluster.

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tze-Chiang Meng was an employee of Proximagen LLC at the time this trial was conducted and is currently an Independent Consultant to Proximagen LLC and Managing Director of T. Meng Consulting, LLC. Jerzy P. Szaflarski has been on scientific advisory boards of GW Pharmaceuticals, SK Life Science, and UCB Pharma; has received research support from the Charles Shor Foundation for Epilepsy Research, Eisai, GW Pharmaceuticals, LivaNova, NeuroPace Inc, Serina Therapeutics, and UCB Pharma; and serves as a scientific advisor to iFovea and AdCel Biopharma. Linda Chen was an employee of UCB Pharma at the time this trial was conducted and is currently an independent researcher. Marcus Brunnert is a salaried employee of UCB Pharma. Rita Campos is a salaried employee of UCB Pharma and receives stock options from her employment. Peter Van Ess was an employee of Proximagen LLC at the time this trial was conducted and is currently Vice President of Early Development, DepYmed, Inc. William E. Pullman was an employee of Proximagen LLC at the time this trial was conducted and is currently an Independent Consultant and President of Pullman Drug Development Consultants, LLC. Toufic Fakhoury has served as a consultant or speaker for or has received research support from Aquestive, Eisai, SK Life Science, Sunovion, and UCB Pharma. Part of this work was presented as a poster at the 74th Annual Meeting of the American Epilepsy Society (virtual meeting); on December 5, 2020.

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