2 Dexmedetomidine Sublingual Film for Acute Agitation in Schizophrenia or Bipolar Disorder by Baseline Clinical Global Impression-Severity of Agitation

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1016/j.annemergmed.2022.08.024

Journal Title

Annals of Emergency Medicine

Department

Psychiatry and Behavioral Sciences

Abstract

Objectives: Dexmedetomidine sublingual film (SF) is a self-administered treatment for acute agitation in patients with schizophrenia (SCZ) or bipolar disorder (BPD). Dexmedetomidine is a selective agonist of alpha-2 adrenergic receptors. A post hoc analysis of pooled Phase 3 clinical trial data investigated the efficacy of dexmedetomidine SF by baseline agitation severity as measured by the clinical global impression- severity (CGI-S) scale. Design/Methods: Two similarly designed, randomized, double-blind, placebo-controlled Phase 3 trials of dexmedetomidine sublingual film (180 mcg or 120 mcg) were conducted in participants aged 18-75 with acute agitation and either SCZ or BPD. Acute agitation was defined as a total score ³14 on the Positive and Negative Syndrome Scale (PANSS)-Excited Component (PEC) scale and ³ 4 on at least 1 of the 5 PEC items (poor impulse control, tension, hostility, uncooperativeness, excitement). The primary endpoint was change from baseline in PEC total at 2h. The secondary endpoint was earliest time of a statistically significant separation from placebo. Severity of agitation at baseline was assessed by the CGI-S scale at Screening and immediately prior to dosing. The CGI-S was focused on the severity of agitation rather than the severity of the overall illness. Results: 760 patients enrolled in the 2 trials. All doses of dexmedetomidine SF met the primary endpoint of statistically significant change from baseline in PEC total at 2h vs placebo (P<.001). Mean (SD) reductions in PEC total at 2h were -10.4 (4.4), -8.7 (5.0), and -4.8 (4.7) for 180 mcg, 120 mcg, and placebo, respectively. Statistically significant separation from placebo occurred as early as 10 minutes at 180 mcg (P=.004) and 20 minutes at 120 mcg (P=.015). The PEC total score and PEC change from baseline were stratified by baseline CGI-S score, mild (2-3), moderate (4), and severe (5-6). Mean (SD) 2-hour PEC total scores for 180 mcg were 5.5 (1.3), 7.5 (3.4), and 8.2 (4.8), for 120 mcg were 7.6 (3.9), 8.8 (4.2), 10.2 (5.7), and for placebo groups were 8.4 (3.6), 12.7 (4.6), and 16.2 (5.4) for those with baseline mild, moderate, and severe CGI-S scores, respectively. Least squares mean difference from placebo for 180 mcg were -3.1 (0.8), -5.0 (0.4), and -8.2 (1.1) (all P<.001) and for 120 mcg were -0.7 (0.9; P=.45), -3.9 (0.4; P<.001),-6.2 (1.1; P<.001) for those with mild, moderate, and severe CGI-S scores, respectively. There were no drug-related serious or severe AEs in either trial. No participant was unarousable either by AE reporting or by the Agitation and Calmness Evaluation Scale (ACES). The most common treatment emergent adverse events (TEAEs) were somnolence (21.5%), dry mouth (5.9%), hypotension (5.3%), dizziness (4.9%), orthostatic hypotension (4.0%), oral hypoesthesia (3.8%), and headache (3.6%). Of 110 somnolence reports, 86% were mild and 14% moderate. Conclusions: Dexmedetomidine sublingual film treated acute agitation associated with SCZ or BPD, with an onset of action as early as 10 minutes at 180 mcg and was well tolerated with somnolence the most common AE. Dexmedetomidine provides a novel mechanism of action, making it a potential addition to noninvasive treatments for acute agitation. Yes, authors have interests to disclose Disclosure: BioXcel Therapeutics Employee BioXcel Therapeutics Disclosure: BioXcel Therapeutics Employee BioXcel Therapeutics Disclosure: BioXcel Therapeutics Employee BioXcel Therapeutics

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