AGItated Patients Management: intraNASAL Midazolam vs Intramuscular Loxapine

Study Overview
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Brief Summary
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This study is a non-inferiority phase III randomized trial evaluating the effect of intranasal midazolam versus intramuscular loxapine on the rapid tranquilization of agitated patient in emergency department. Intranasal midazolam is safe and may allow a management of extreme agitation state and prevent adverse effects.

Detailed Description
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This study is a prospective, multicenter, open-label randomized, controlled, parallel-group 2-arm phase III non-inferiority trial. Patients with agitation at emergency department will be randomized to two arms of treatment: one experimental arm with intranasal midazolam 5mg (investigational medicinal product), and one control arm with comparator treatment intramuscular loxapine 100mg. The duration of participation for each patient is at least 28 days (+7 days if follow-up not completed on D28). An endpoint Adjudication Committee will be scheduled.

Official Title
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AGItated Patients Management: intraNASAL Midazolam vs Intramuscular Loxapine, a Randomized Non Inferiority Trial

Conditions
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Emergence Delirium

Intervention / Treatment
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* Drug: Intranasal midazolam
* Drug: Intramuscular loxapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 60 years; Agitated Patient whose somatic or psychiatric aetiology cannot be diagnosed in an emergency situation and who need a sedation in a hospital emergency setting due to the presence of unmanageable agitation with 3 major criteria. Major criteria : Agitation Pain Tolerance Tachypnea ( fr > 20) And 1 minor criteria among : Sweating Tactile Hyperthermia Medical care Non compliance Lack of tiring Unusual Strenght Inappropriately clothed, nudity • Medical insurance The protocol can start if the THREE major inclusion criteria and ONE of the minor inclusion criteria are checked PRESENT and ALL the non-inclusion criteria are checked no. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from randomization into the study: Pregnancy Prisoners Contraindications to intranasal Midazolam or intramuscular Loxapine : Hypersensitivity to benzodiazepines or to any of the excipients (Sodium Chloride, Hydrochloric Acid, Sodium Hydroxide, Water for Injection) Known hypersensitivity to loxapine or to any of the excipients (Polysorbate 80, propylene glycol, 20% v/v hydrochloric acid, water for injections, Nitrogen (Inert gas) Individuals who are in comatose states or have central nervous system (CNS) depression due to alcohol or are taking other depressant drugs Individuals with severe depressive states, spastic diseases, and with Parkinson's disease, except in the case of dyskinesias due to levodopa treatment In combination with dopamine agonists except levodopa (amantadine, bromocriptine, lisuride, pergolide, piribedil, ropinirole, cabergoline, pramipexole, apomorphine) outside the patient with Parkinson's disease Individuals with a history of cerebrovascular accident or epilepsia Individuals in whom a significant elevation of blood pressure would constitute a serious hazard, such as patients with significant hypertension; Individuals with severe cardiac decompensation Patients with severe respiratory failure or acute respiratory depression Individuals with acute narrow angle glaucoma.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Intramuscular loxapine versus intranasal midazolam
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intranasal midazolam<br>Midazolam, 5 mg, injectable solution in 5mg/ml, if weight < 50 kg : 5mg; if weight ≥50kg : 10mg, intranasal administration, atomize into nose with Mucosal Atomizer Device (MAD) 5mg(1ml) up each nostril , one time | Drug: Intranasal midazolam<br>* Midazolam, 5 mg, injectable solution in 5mg/ml, intranasal administration, atomize into nose with Mucosal Atomizer Device (MAD) 5mg(1ml) up each nostril , one time<br>* Other names: Midazolam;|
| Active Comparator: Intramuscular loxapine<br>Loxapine, 100mg, injectable solution in 50mg/2ml intramuscular, intra muscular administration, one time | Drug: Intramuscular loxapine<br>* Loxapine, 100mg, injectable solution in 50mg/2ml intramuscular, intra muscular administration, one time<br>* Other names: Loxapine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of agitation | The proportion of patients with sufficient improvement of agitation at 15 minutes defined by a reduction of at least 3 points on the CGI (Clinical Global Impression). | 15 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events following the use of loxapine or midazolam | The adverse effects over 240 minutes : oxygen desaturation [<90%], airway obstruction requiring intervention, tracheal intubation, cardiac arrhythmias, prolonged QTc interval, hypotension, extrapyramidal side effects, akathisia, and anaphylaxis. | 240 minutes | 
| Number of deceased patients | mortality at 24 hours | 24 hours | 
| Number, type and severity level of adverse events | The adverse effects over 240 minutes : oxygen desaturation [<90%], airway obstruction requiring intervention, tracheal intubation, cardiac arrhythmias, prolonged QTc interval, hypotension, extrapyramidal side effects, akathisia, and anaphylaxis | 240 minutes | 
| level of sedation obtained by loxapine or midazolam. | The proportion of patients with sufficient improvement of agitation at 240 minutes defined by a reduction of at least 3 points on the CGI. Proportion of patients clinically improved on the improvement subscale of the clinical global impressions scale at 15, 60, 120, and 240 minutes. | 15,60,120 and 240 minutes | 
| level of sedation obtained by loxapine or midazolam. | Proportion of patients with additional sedation required | 15 minutes | 
| feelings of health providers with Qualitative research. | Duration of violent and acute behavioural disturbance Staff injuries. Proportion of patients requiring the doctor to be called back. | 15 min and 240 min | 
| Improvement of agitation | The proportion of patients with sufficient improvement of agitation at 15 minutes defined by a RASS < -1 | 15 min |