Efficacy and safety of Remimazolam compared to Ketamine and Propofol in Rapid Sequence Induction. A monocentric pilot randomised-controlled study

The primary objective is to compare the ability of remimazolam to standard doses of propofol and ketamine to achieve successful tracheal intubation on the first attempt in patients at risk of aspiration of gastric contents in the operating room. This comparison is clinically relevant as it evaluates the efficacy of remimazolam as an alternative induction agent in rapid sequence induction, a critical procedure in patients requiring urgent airway management with elevated aspiration risk.

The secondary objectives include:

• Comparison of the efficacy of remimazolam, propofol and ketamine by assessing quality of intubation conditions, timing of tracheal intubation, mechanical or respiratory complications, and cardiovascular complications.

• Comparison of the tolerance of remimazolam, propofol and ketamine by evaluating episodes of delirium in recovery room, episodes of acute renal failure, and death.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of both **female** and **male** participants aged between **18 and 80 years**. Eligible participants were patients requiring **orotracheal intubation** during **general anaesthesia** in the **operating room** and presented at least one risk factor for **aspiration of gastric contents**. These risk factors included a **preoperative fasting** period of less than 6 hours, **occlusive syndrome**, **functional ileus**, **vomiting** episode within the last 12 hours, **orthopaedic trauma** within the last 12 hours, or a medical history of symptomatic **gastroesophageal reflux**, **hiatus hernia**, **gastroparesis**, **dysautonomia**, or gastroesophageal surgery with **sphincter dysfunction**. Participants or their next of kin provided written **informed consent**, or an emergency procedure was followed when applicable. The trial population was selected based on the presence of these specific clinical conditions that increase the risk of aspiration during **rapid sequence induction** in the operating room setting.

This clinical trial is designed as a **monocentric**, **randomized**, **controlled** pilot study to evaluate the efficacy and safety of **remimazolam** compared to **ketamine** and **propofol** in **rapid sequence induction** in the operating room. The trial is classified as **phase IV** and follows an exploratory phase II methodology. The main objective is to compare the ability of remimazolam to standard doses of propofol and ketamine to achieve successful **tracheal intubation** on the first attempt in patients at risk of **aspiration of gastric contents** in the operating room. The study involves three test products administered via **intravenous injection**: propofol at a maximum daily dose of 4 mg/kg, ketamine at a maximum daily dose of 3 mg/kg, and remimazolam (Byfavo 20 mg powder for solution for injection) at a maximum daily dose of 0.4 mg/kg. Each product has a maximum treatment period of one day. The trial is expected to commence recruitment on March 30, 2026, and conclude on April 30, 2027.

The study population includes female and male participants between 18 and 80 years of age who require **orotracheal intubation** during **general anaesthesia** in the operating room and have at least one risk factor for aspiration of gastric contents. Risk factors include a preoperative fasting period of less than 6 hours, **occlusive syndrome**, **functional ileus**, vomiting episode within the last 12 hours, **orthopaedic trauma** within the last 12 hours, or medical history of symptomatic **gastroesophageal reflux**, **hiatus hernia**, **gastroparesis**, **dysautonomia**, or gastroesophageal surgery with sphincter dysfunction. Written informed consent from the patient or their next of kin, or an emergency procedure, is required for participation.

The **primary endpoint** is the proportion of patients with successful intubation at first attempt. **Secondary endpoints** assessed in the operating theatre within 5 minutes after induction of anaesthesia include median **intubation quality score** (IDS-3) values, median **Cormack-Lehane score** values, median **POGO score** values, median time between start of pre-oxygenation, administration of hypnotic, administration of **neuromuscular blocker**, initiation of first **laryngoscopy**, and tracheal intubation, median values of **heart rate**, **mean arterial pressure**, and **SpO2** measured every minute during the first 5 minutes, percentage of patients with pulmonary aspiration of gastric contents, percentage of patients with moderate or severe **desaturation**, median minimal SpO2 value, percentage of patients with major **cardiovascular events** including **hemodynamic instability**, **cardiac arrhythmia**, percentage of patients with **anaphylaxis reaction**, rates of **vasopressor** use and volume of intravenous fluids for vascular filling, and total dose of hypnotic used. In the recovery room, secondary endpoints include postoperative **Nu-DESC score** median value and percentage of patients requiring sedative therapy assigned with **delirium**. Up to day 7, secondary endpoints include percentage of patients with major cardiovascular complications, percentage of patients with postoperative **acute renal failure** at day 7, intra-hospital mortality, and survival proportion at day 7.

Participant involvement is limited to the perioperative period, encompassing the operating theatre and recovery room assessments, with follow-up extending up to day 7 postoperatively. Early termination from the study may occur under conditions requiring withdrawal of consent, occurrence of serious adverse events, or at the discretion of the investigator based on safety concerns or protocol deviations.

This clinical trial investigates three experimental medications for rapid sequence induction in patients at risk of aspiration of gastric contents. All investigational products are administered via **intravenous injection** for a maximum treatment period of one day.

**Byfavo** 20 mg powder for solution for injection contains **remimazolam** as the active substance. The product is supplied as a powder for solution for injection and is administered as a solution for injection. The maximum daily dose is 0.4 mg/kg, with a maximum total dose of 0.4 mg/kg. The product holds marketing authorization number EU/1/20/1505/001 and is manufactured by PAION PHARMA GMBH. Remimazolam is classified under ATC code N05CD14.

**Propofol** is administered as an injection formulation. The active substance is propofol, a chemical compound. The maximum daily dose is 4 mg/kg, with a maximum total dose of 4 mg/kg. The route of administration is intravenous injection.

**Ketamine** is administered as a solution for injection. The active substance is ketamine, a chemical compound. The maximum daily dose is 3 mg/kg, with a maximum total dose of 3 mg/kg. The route of administration is intravenous injection.

All three investigational products are classified as test medications in this trial and are used to compare their ability to achieve successful tracheal intubation on the first attempt. None of the products are paediatric formulations. Dosing is weight-based and expressed in milligrams per kilogram of body weight.

Efficacy will be assessed through the evaluation of intubation success and quality parameters in the operating theatre. The primary endpoint is the proportion of patients with successful intubation at first attempt. Secondary endpoints include median intubation quality score (IDS-3) values, median Cormack-Lehane score values, and median percentage of glottic opening (POGO) score values, all measured within 5 minutes after induction of anesthesia. Additional efficacy parameters encompass median time intervals between start of pre-oxygenation, administration of hypnotic, administration of neuromuscular blocking agent, initiation of first laryngoscopy, and tracheal intubation defined as the 6th capnography curve, measured in minutes.

Further efficacy assessments include median values of heart rate, mean arterial pressure, and SpO2 measured every minute from pre-oxygenation during the first 5 minutes after anesthetic induction. The percentage of patients with pulmonary aspiration of gastric contents, percentage of patients with moderate (SpO2 ≤ 95%) or severe (SpO2 ≤ 80%) desaturation, and median minimal value of SpO2 during the first 5 minutes after anesthetic induction will be evaluated. The percentage of patients with major cardiovascular events, including major hemodynamic instability defined as mean arterial pressure ≤ 60 mmHg or ≤ 40% from the patient's reference value, heart rate < 45/min, or systolic arterial pressure < 80 mmHg, cardiac arrhythmia requiring pharmacological or external electric intervention or lasting more than 30 seconds, will be assessed. The percentage of patients with anaphylaxis reaction and grade of anaphylaxis reaction, rates of vasopressor use and volume of intravenous fluids for vascular filling from entry into the operating theatre to induction and from induction to recovery room, and the total dose of hypnotic used during the first 5 minutes after anesthetic induction will be recorded.

In the recovery room, postoperative Nu-DESC score median value and percentage of patients requiring sedative therapy in recovery room assigned with delirium will be evaluated. Up to day 7, the percentage of patients with major cardiovascular complications, percentage of patients with postoperative acute renal failure at day 7, intra-hospital mortality, and survival proportion at day 7 will be assessed. All efficacy parameters will be compared between the three study groups.