AGItated Patients Management: intraNASAL Midazolam vs Intramuscular Loxapine (AGINASAL)

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

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.

Study Overview

• Status: Terminated
• Conditions: Emergence Delirium
• Intervention / Treatment: Drug: Intranasal midazolam; Drug: Intramuscular loxapine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93000
    • Hôpital Avicenne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intranasal midazolam; 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; 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; Other Names: Midazolam
Active Comparator: Intramuscular loxapine; Loxapine, 100mg, injectable solution in 50mg/2ml intramuscular, intra muscular administration, one time	Drug: Intramuscular loxapine; Loxapine, 100mg, injectable solution in 50mg/2ml intramuscular, intra muscular administration, one time; Other Names: Loxapine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Lariboisière-Saint Louis clinical research unit
• Investigators: Principal Investigator: Frédéric Adnet, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2023
• Primary Completion (Actual): April 9, 2023
• Study Completion (Actual): April 23, 2024

Study Registration Dates

• First Submitted: March 21, 2022
• First Submitted That Met QC Criteria: April 11, 2022
• First Posted (Actual): April 12, 2022

Study Record Updates

• Last Update Posted (Actual): May 28, 2024
• Last Update Submitted That Met QC Criteria: May 23, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Emergence Delirium; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Loxapine
• Other Study ID Numbers: P160947J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No