Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial

Abstract

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior.

Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder.

Design, setting, and participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study.

Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126).

Main outcomes and measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025.

Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 μg, -9.0 for sublingual dexmedetomidine 120 μg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 μg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 μg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 μg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%).

Conclusions and relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size.

Trial registration: ClinicalTrials.gov Identifier: NCT04276883.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Preskorn reported receiving consulting fees from BioXcel Therapeutics Inc; receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr Zeller reported receiving personal fees from BioXcel Therapeutics outside the submitted work. Dr Citrome reported receiving fees for serving as the chair of the drug monitoring committee of BioXcel for this study; serving as a consultant for BioXcel for work outside this study and from AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, Boehringer Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, Medavante-ProPhase, Merck, Neurocrine, Noven, Osmotica, Otsuka, Ovid, Relmada, Sage, Sunovion, Takeda, Teva, and the University of Arizona; serving as a speaker for AbbVie, Acadia, Alkermes, Allergan, Angelini, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sunovion, Takeda, and Teva; participating in continuing medical education activities organized by Medscape, the North American Center for Continuing Medical Education, Neuroscience Education Institute, and Vindico; owning stocks in Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer; serving as editor-in-chief of the International Journal of Clinical Practice through 2019; serving as a reviewer for UpToDate and Springer Healthcare; and being a topic editor for Psychiatry, Clinical Therapeutics. Dr Finman reported receiving personal fees from Cognitive Research Corporation for statistical consulting on this study and for statistical consulting for other studies outside the submitted work. Dr Goldberg reported serving on the speakers bureau of Allergan, Intracellular Therapies, and Sunovion; serving as a consultant for BioXcel, Lundbeck, and Otsuka; receiving fees for serving on the drug monitoring committee for this study and serving as a consultant outside the submitted work for BioXcel; and receiving royalties from American Psychiatric Publishing and Cambridge University Press. Dr Fava reported receiving research support from Abbott Laboratories, Acadia, Alkermes, American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir, Axsome, Biohaven, BioResearch, BrainCells Inc, Bristol Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clarus Funds, Clintara, Covance, Covidien, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, Ganeden Biotech, GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen, Jed Foundation, Johnson & Johnson, Lichtwer Pharma GmbH, Lorex, Lundbeck, Marinus, MedAvante, Methylation Science, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, National Coordinating Center for Integrated Medicine, National Institute of Drug Abuse, National Institute of Mental Health, Neuralstem, NeuroRx Novartis AG, Organon, Otsuka, PamLab, Pfizer, Pharmacia-Upjohn, Pharmaceutical Research Associates, Pharmavite, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, Roche, RCT Logic (formerly Clinical Trials Solutions), Sanofi-Aventis US, Shire, Solvay, Stanley Medical Research Institute, Synthelabo, Taisho, Takeda, Tal Medical, VistaGen, and Wyeth-Ayerst; serving on the advisory board of or as a consultant to Abbott, Acadia, Affectis, Alkermes, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Avanir, Axsome Therapeutics, Bayer, Best Practice Project Management, Biogen, BioXcel Therapeutics, BioMarin, Biovail, Boehringer Ingelheim, Boston Pharmaceuticals, BrainCells, Bristol Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, CNS Response, Compellis, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dinippon Sumitomo, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, EnVivo, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Grunenthal GmbH, Indivior, i3 Innovus/Ingenis, Intracellular, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Knoll Pharmaceuticals, Labopharm Inc, Lorex, Lundbeck, Marinus, MedAvante, Merck, MSI Methylation Sciences, Naurex, Navitor Pharmaceuticals, Nestle Health Sciences, Neuralstem, Neuronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21, Orexigen, Organon, Osmotica, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx, Praxis Precision Medicines, Precision Human Biolaboratory, Prexa, PPD, Purdue Pharma, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT Logic (formerly Clinical Trials Solutions), Relmada Therapeutics, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche, Sanofi-Aventis, Sensoritum, Sepracor, Servier Laboratories, Schering-Plough, Shenox, Solvay, Somaxon, Somerset Pharmaceuticals, Sunovion, Supernus, Synthelabo, Taisho , Takeda, Tal Medical, Tetragenex, Teva, TransForm Pharmaceuticals, Transcept Pharmaceuticals, Usona Institute, Vanda, Versant Venture Management, and VistaGen; being a speaker for or publishing with Adamed Co, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol Myers Squibb, Cephalon, the CME Institute of the Physicians Postgraduate Press, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Imedex, Massachusettes General Hospital (MGH) Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; having stock or equity in Compellis, PsyBrain, and Sensorium Therapeutics; having a patent for Sequential Parallel Comparison Design, licensed by MGH to PPD and an application pending for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and patents for pharmacogenomics of Depression Treatment with Folate. Dr Kakar reported being the principal investigator for the sublingual dexmedetomidine clinical research program and having served as a consultant for Neurocrine Biosciences, Alkermes, and Otsuka. Dr De Vivo reported being an employee of and having a patent pending with BioXcel Therapeutics. Dr Risinger reported being an employee of BioXcel Therapeutics and having pending patents issued to BioXcel for sublingual dexmedetomidine. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Follow-up of Patientsa

aThis was a single-dose study, and the safety, full analysis, and per-protocol data sets all contained 378 patients—126 in each group. There were no missing data for the primary or secondary outcome measures. One patient each from 180 μg and 120 μg groups did not receive a dose of medication, but all other discontinuations occurred after dosing and primary and secondary end point assessments. bOne hundred thirteen patients (89.7%) received only 1 dose; 5 (4%), 2 doses; and 8 (6.3%), 3 doses. cNinety-six patients (76.2%) received only 1 dose; 18 (14.7%), 2 doses; and 12 (9.5%), 3 doses. dSixty-eight patients (54%) received only 1 dose; 29 (23.0%), 2 doses; and 29 (23%), 3 doses. eDue to acute agitation on day 7 that was judged to be unrelated to study drug.

Figure 2.. Mean Change From Baseline in the Positive and Negative Syndrome Scale-Excited Component Total Score Through 2 Hours

Dark squares in boxes indicate the mean; the top box lines, upper quartile; the bottom box line, lower quartile; bars in boxes, median; whiskers, data falling within 1.5 times the interquartile range; dots, values outside the range indicated by the whiskers; and PEC, Positive and Negative Syndrome Scale-Excited Component.