Impact of CES1 Genotype on Remimazolam

Recruiting

• Conditions: Adult; Middle Aged; Elective Surgical Procedures
• Interventions: Drug: Remimazolam besylate

• Registration Number: NCT05841667
• Lead Sponsor: Korea University Guro Hospital

Brief Summary

Remimazolam is primarily metabolized via CES1, and other drugs that are commonly metabolized by CES1 are known to have their pharmacokinetics and clinical effects affected by genetic polymorphisms in CES1.

The goal of this observational study is to investigate the impact of the CES1 genotype on the pharmacokinetics, safety, and efficacy of remimazolam in patients undergoing elective surgery.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-04-10
• Study First Submitted QC: 2023-04-24
• Study First Posted: 2023-05-03
• Study Start: 2023-09-06
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-09
• Last Update Posted: 2024-10-14
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

• American Society of Anesthesiologists (ASA) physical status 1 or 2
• Age 19-70 years
• Elective surgery

Read More

Exclusion Criteria

• Concomitant regional anesthesia
• Uncontrolled hypertension (systolic blood pressure >180 mmHg)
• Uncontrolled diabetes mellitus (HbA1c >9.0%)
• Aspartate transaminase (AST), Alanine transferase (ALT), Total bilirubin > more than 2 times the normal upper limit
• Estimated glomerular filtration rate <60 ml/min/1.73m2
• Moderate to severe chronic pulmonary obstructive disease or respiratory failure
• Emergency
• Hepatectomy, Liver transplantation
• Cardiopulmonary bypass use
• Craniotomy due to head trauma, unstable intracranial pressure, or brain disease
• Use of benzodiazepine medications (if tolerance is present)
• Anxiety, alcohol/drug dependence, or addiction to tricyclic antidepressants
• Reported hypersensitivity and adverse reactions to benzodiazepines, flumazenil, and other agents used during anesthesia
• Lactose-related genetic disorders
• Myasthenia gravis or myasthenia gravis syndrome
• Newly diagnosed myocardial infarction/clinically significant coronary artery disease, cerebral ischemic attack/stroke within 6 months, or significant untreated coronary artery disease
• Implanted rate-responsive cardiac pacemaker with a bioelectrical impedance sensor.
• Intrinsic brain disorders or other conditions that make it difficult to determine the depth of anesthesia through EEG measurements (e.g., epilepsy)
• History of severe allergies
• Cognitive impairment that prevents comprehension of the instructions and consent form of this study, in case of sedation
• Expected intraoperative blood loss of 1000 ml or more
• Judged by the investigator to be unsuitable for participation in this study due to other reasons

Read More

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
CES1 without or without single nucleotide polymorphism (SNP)	Remimazolam besylate	We will determine the CES1 genotype of participants through a laboratory test. Several different types of SNPs can be identified, and analyses can be further stratified by CES1 SNP type.

Primary Outcome Measures

Name	Time	Method
Dose-adjusted steady-state concentration of remimazolam	Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam	Determine the dose-adjusted steady-state concentration of remimazolam using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS)
Maintenance dose of remimazolam for maintaining general anesthesia	Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam	Hourly maintenance dose of remimazolam for maintaining general anesthesia
Total dose of remimazolam used to induce general anesthesia	Initiation of remimazolam administration ~ 5 minutes after start of remimazolam	Determine the total dose of remimazolam to achieve loss of consciousness (LOC). Modified Observer's Alertness/Sedation Scale (MOAA/S) \<2 indicates LOC. The MOAA/S scale assesses a patient's level of alertness and response to stimulation, and is scored on a 6-point scale (6: awake and alert, 1: deeply asleep and unresponsive to any stimulus).

Secondary Outcome Measures

Name	Time	Method
Percentage maintained BIS >60 during general anesthesia	Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration)	Calculate "Time maintained BIS \>60 / Time remimazolam administered"
Total dose of remifentanil during general anesthesia	Initiation of remifentanil administration ~ Cessation of remifentanil(up to 10 hours after start of remifentanil administration)	Determine the total dose of remifentanil during general anesthesia
Changes in BIS during induction and maintenance of anesthesia	Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam	Measure BIS during anesthesia
Time to LOC after remimazolam administration during anesthesia induction	Initiation of remimazolam administration ~ 5 minutes after start of remimazolam	Determine the time to achieve LOC after remimazolam dosing.
Time to bispectral index(BIS) < 60 after remimazolam administration during anesthesia induction	Initiation of remimazolam administration ~ 10 minutes after start of remimazolam	Determine the time to achieve BIS \<60 after remimazolam dosing
Changes in BIS during anesthesia induction and maintenance	Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam	Assess BIS values during general anesthesia
Postanesthesia care unit (PACU) length of stay	PACU admission ~ PACU discharge (within 3 hours after PACU admission)	Determine how long participants stay in the PACU before being transferred to a general ward
Emergence delirium	Immediately after extubation ~ 3 hours after PACU admission	Richmond Agitation Sedation Scale (RASS) ≥1 indicates emergence delirium (RASS score ranges from -5 to +4, with negative numbers indicating varying degrees of sedation or lethargy, and positive numbers indicating varying degrees of agitation or restlessness)
Resedation	Immediately after extubation ~ 3 hours after PACU admission	Richmond Agitation Sedation Scale (RASS) ≤-2 indicates resedation
Precipitation	Initiation of remimazolam administration ~ 10 minutes after start of remimazolam	Visually determine whether remimazolam administration causes precipitation in the fluid line through which the agent is administered
Injection pain caused by remimazolam administration	Initiation of remimazolam administration ~ 3 minutes after start of remimazolam	Question the patient to determine if pain occurs at the intravenous site where remimazolam is administered (check only if it occurs)
Adverse events up to 48 hours after surgery	Initiation of remimazolam administration ~ 48 hours after surgery	All adverse events including nausea/vomiting, hypertension/hypotension(30% or more change in preoperative blood pressure), bradycardia (heart rate \<50 beats per minute\[bpm\]), tachycardia (heart rate \>100 bpm)
Endogenous metabolites that occur as remimazolam is metabolized in the body (This is an exploratory check, meaning we do not know in advance what substances will be found)	Immediately before the start of remimazolam ~ 120 minutes after remimazolam cessation	Analyze collected blood and urine to determine the metabolites of remimazolam (Therefore, various laboratory methods can be used to detect endogenous metabolites, but it is not known in advance exactly how)
Total dose of remimazolam during general anesthesia	Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration)	Determine the total dose of remimazolam during general anesthesia
Operation time	Start of surgery ~ End of surgery(up to 10 hours after start of surgery)	Determine how long the surgery was performed
Anesthesia time	Initiation of remimazolam administration ~ Exit to the PACU (within 30 minutes after remimazolam cessation)	Determine how long the general anesthesia was performed
Flumazenil dosage	Cessation of remimazolam ~ 30 minutes after remimazolam cessation	If the participants are not awake within 10 minutes after discontinuation of remimazolam, administer flumazenil and verify the total dosage (max: 1 mg).
Pain score in PACU	PACU admission ~ PACU discharge (within 3 hours after PACU admission)	If the participants are able to verbalize their pain, use a Numerical Rating Scale (NRS), otherwise use a Visual Analog Scale (VAS). Both scales are used to measure pain intensity on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Analgesic usage in PACU	PACU admission ~ PACU discharge (within 3 hours after PACU admission)	Identify the type and dose of opioid or non-opioid pain medication used to control the participants' pain.
Delirium	After surgery ~ Hospital discharge (within 1 month after surgery)	Determine delirium during post-operative hospitalization through electronic medical records
Postoperative complications	After surgery ~ Hospital discharge (within 1 month after surgery)	Identify any complications during post-operative hospitalization through electronic medical records
Hospital stay after surgery	The day of surgery ~ Hospital discharge (within 1 month after surgery)	Identify the hospital length of stay after surgery

Trial Locations

Locations (1)

Korea University Guro Hospital; 🇰🇷 Seoul, Korea, Republic of