Efficacy of Sublingual Dexmedetomidine and Buccal Midazolam Versus Oral Lorazepam for Acute Agitation Management in Emergency Psychiatry

The primary objective of this study is to evaluate the **efficacy** of a single dose of sublingual **dexmedetomidine** compared to oral **lorazepam**, and a single dose of buccal **midazolam** compared to oral lorazepam for acute tranquillization in patients experiencing **acute agitation**. This is clinically relevant as it aims to identify more effective and rapid-acting treatments for managing acute agitation, which is a common and challenging condition in emergency psychiatry.

Secondary objectives include examining the effectiveness, tolerability, safety, and patient-reported satisfaction of the aforementioned treatments. These aspects are crucial for understanding the overall benefit-risk profile of the treatments and their acceptability to patients, which can inform clinical decision-making and improve patient care in emergency settings.

The clinical trial focuses on individuals experiencing **acute agitation** and aims to evaluate the efficacy of different tranquillization methods. The study population includes both male and female participants aged between 18 and 64 years, who are in need of tranquillization in inpatient psychiatric settings, including psychiatric emergency rooms. Participants are required to have a total score of 14 or higher on the PANSS Excited Component (PEC) and a score of 4 or higher on at least one of the five items of the PEC. Informed consent must be obtained prior to the occurrence of the emergency. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **dexmedetomidine** in sublingual film form and **midazolam** in buccal solution form compared to **lorazepam** tablets for the treatment of acute agitation in psychiatric settings. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment is being administered, thereby minimizing bias. The trial is expected to commence recruitment on November 1, 2024, and conclude by December 31, 2027. Participants will be involved in the study for a maximum of one day, as the treatment period is limited to a single dose administration.

Study visits will follow a structured sequence, beginning with an inclusion visit where participants are screened based on specific criteria, including age (18-64 years), a need for tranquillization, and a PANSS Excited Component (PEC) score of 14 or higher. Informed consent must be obtained prior to the emergency occurrence. Following the inclusion visit, participants will receive a single dose of the assigned medication. The primary endpoint is the change in PEC score at 60 minutes post-dose, with secondary endpoints including the earliest time a significant difference in agitation is observed, proportion of participants tranquillized or asleep, and patient-reported satisfaction.

Follow-up visits will occur at 30, 60, 90, and 120 minutes post-dose to assess the change in agitation levels and other secondary outcomes. The end-of-study visit will coincide with the final assessment at 120 minutes post-dose. Participants may be withdrawn from the study if they require rescue medication within 4-12 hours post-dose or if they experience adverse events that necessitate discontinuation. The trial aims to provide valuable insights into the comparative effectiveness of these medications in managing acute agitation, contributing to improved treatment strategies in emergency psychiatric care.

The clinical trial involves the administration of three different treatments to evaluate their efficacy in managing **acute agitation** in emergency psychiatry. The first treatment is **Lorazepam Orion 1 mg tabletter**, which contains the active substance **lorazepam**. This medication is provided in tablet form and is administered orally. The maximum daily dose is 8 mg, with a total treatment period of one day. Lorazepam is a benzodiazepine, commonly used for its anxiolytic and sedative properties, and is manufactured by Orion Corporation.

The second treatment is **Midazolam Medical Valley 10 mg munhålelösning**, which contains the active substance **midazolam**. This medication is formulated as an oromucosal solution and is administered via buccal use. The maximum daily dose is 20 mg, with a total treatment period of one day. Midazolam is a short-acting benzodiazepine, known for its sedative and anxiolytic effects, and is produced by Medical Valley Invest AB.

The third treatment is **Igalmi**, which contains the active substance **dexmedetomidine**. This medication is provided as a sublingual film and is administered sublingually. The maximum daily dose is 270 µg, with a total treatment period of one day. Dexmedetomidine is an alpha-2 adrenergic agonist, used for its sedative and analgesic properties, and is manufactured by Region Hovedstadens Apotek.

In this trial, **Lorazepam Orion** serves as the comparator treatment, while **Midazolam Medical Valley** and **Igalmi** are the test treatments. The trial aims to compare the efficacy of a single dose of sublingual dexmedetomidine and buccal midazolam against oral lorazepam for acute tranquillization. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedules and administration routes.

The efficacy of treatments in this clinical trial will be assessed by comparing the effects of a single dose of sublingual **dexmedetomidine** and buccal **midazolam** against oral **lorazepam** for acute tranquillization in patients experiencing agitation in psychiatric settings. The primary endpoint for evaluating efficacy is the change in the PANSS Excited Component (PEC) score at 60 minutes post-dose, compared to pre-dose levels. Secondary endpoints include the earliest time at which a statistically significant difference in agitation is observed, as measured by changes in the PEC score at 30, 60, 90, and 120 minutes post-dose. Additional secondary endpoints involve the proportion of patients who are tranquillized or asleep, as indicated by a score of ≤4 on the Behavioral Activity Rating Scale (BARS) at specified time intervals, and the proportion of patients who are physically or mechanically restrained or require rescue medication within 12 hours post-dose. Patient-reported satisfaction will also be measured using selected items from the Treatment Satisfaction Questionnaire for Medication II.