Impact of CES1 Genotype on Remimazolam

A Clinical Study to Explore the Effect of Carboxylesterase 1 (CES1) Genotype on Pharmacokinetics, Safety, and Efficacy of Remimazolam

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.

Study Overview

• Status: Recruiting
• Conditions: Adult; Middle Aged; Elective Surgical Procedures
• Intervention / Treatment: Drug: Remimazolam besylate

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Hye Bin Kim, MD, PhD; Phone Number: 82-10-9183-5617; Email: aneshbkim@gmail.com
• Study Contact Backup: Name: Byung Gun Lim, MD, PhD; Phone Number: 82-2-2626-1437; Email: bglim9205@korea.ac.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 08308
    • Recruiting
    • Korea University Guro Hospital
    • Contact: Hye Bin Kim, MD, PhD; Phone Number: 821091835617; Email: anesbhkim@gmail.com
    • Contact: Byung Gun Lim, MD, PhD; Phone Number: 821038289205; Email: bglim9205@korea.ac.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study will be conducted on adult patients aged 19-64 years, ASA physical status 1-2, undergoing elective surgery in the operating room of Korea University Guro Hospital.

Description

Inclusion Criteria:

• American Society of Anesthesiologists (ASA) physical status 1 or 2
• Age 19-64 years
• Elective surgery

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

CES1 without or without single nucleotide polymorphism (SNP); 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.

Drug: Remimazolam besylate; This is an observational study, meaning that no interventions are actually administered to the participants. However, blood and urine samples will be collected for research purposes. Participants will receive remimazolam besylate for at least 2 hours during anesthesia and surgery. Blood will be drawn to determine the concentration of remimazolam in the blood at the following time points: (1) before remimazolam administration, (2) after remimazolam administration has lasted at least 2 hours without a change in concentration, (3) immediately before discontinuation of remimazolam if there has been a change in concentration since the second blood draw, (4) within 5 minutes of discontinuation, (5) within 15-60 minutes of discontinuation, and (6) 90 minutes after discontinuation. Urine will also be collected after the end of anesthesia to check for metabolites of remimazolam.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-adjusted steady-state concentration of remimazolam	Determine the dose-adjusted steady-state concentration of remimazolam using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS)	Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam
Maintenance dose of remimazolam for maintaining general anesthesia	Hourly maintenance dose of remimazolam for maintaining general anesthesia	Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam
Total dose of remimazolam used to induce general anesthesia	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).	Initiation of remimazolam administration ~ 5 minutes after start of remimazolam

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to LOC after remimazolam administration during anesthesia induction	Determine the time to achieve LOC after remimazolam dosing.	Initiation of remimazolam administration ~ 5 minutes after start of remimazolam
Time to bispectral index(BIS) < 60 after remimazolam administration during anesthesia induction	Determine the time to achieve BIS <60 after remimazolam dosing	Initiation of remimazolam administration ~ 10 minutes after start of remimazolam
Changes in BIS during induction and maintenance of anesthesia	Measure BIS during anesthesia	Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam
Percentage maintained BIS >60 during general anesthesia	Calculate "Time maintained BIS >60 / Time remimazolam administered"	Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration)
Changes in BIS during anesthesia induction and maintenance	Assess BIS values during general anesthesia	Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam
Postanesthesia care unit (PACU) length of stay	Determine how long participants stay in the PACU before being transferred to a general ward	PACU admission ~ PACU discharge (within 3 hours after PACU admission)
Emergence delirium	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)	Immediately after extubation ~ 3 hours after PACU admission
Resedation	Richmond Agitation Sedation Scale (RASS) ≤-2 indicates resedation	Immediately after extubation ~ 3 hours after PACU admission
Precipitation	Visually determine whether remimazolam administration causes precipitation in the fluid line through which the agent is administered	Initiation of remimazolam administration ~ 10 minutes after start of remimazolam
Injection pain caused by remimazolam administration	Question the patient to determine if pain occurs at the intravenous site where remimazolam is administered (check only if it occurs)	Initiation of remimazolam administration ~ 3 minutes after start of remimazolam
Adverse events up to 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)	Initiation of remimazolam administration ~ 48 hours after surgery
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)	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)	Immediately before the start of remimazolam ~ 120 minutes after remimazolam cessation
Total dose of remimazolam during general anesthesia	Determine the total dose of remimazolam during general anesthesia	Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration)
Total dose of remifentanil during general anesthesia	Determine the total dose of remifentanil during general anesthesia	Initiation of remifentanil administration ~ Cessation of remifentanil(up to 10 hours after start of remifentanil administration)
Operation time	Determine how long the surgery was performed	Start of surgery ~ End of surgery(up to 10 hours after start of surgery)
Anesthesia time	Determine how long the general anesthesia was performed	Initiation of remimazolam administration ~ Exit to the PACU (within 30 minutes after remimazolam cessation)
Flumazenil dosage	If the participants are not awake within 10 minutes after discontinuation of remimazolam, administer flumazenil and verify the total dosage (max: 1 mg).	Cessation of remimazolam ~ 30 minutes after remimazolam cessation
Pain score in PACU	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.	PACU admission ~ PACU discharge (within 3 hours after PACU admission)
Analgesic usage in PACU	Identify the type and dose of opioid or non-opioid pain medication used to control the participants' pain.	PACU admission ~ PACU discharge (within 3 hours after PACU admission)
Delirium	Determine delirium during post-operative hospitalization through electronic medical records	After surgery ~ Hospital discharge (within 1 month after surgery)
Postoperative complications	Identify any complications during post-operative hospitalization through electronic medical records	After surgery ~ Hospital discharge (within 1 month after surgery)
Hospital stay after surgery	Identify the hospital length of stay after surgery	The day of surgery ~ Hospital discharge (within 1 month after surgery)

Collaborators and Investigators

• Sponsor: Korea University Guro Hospital
• Investigators: Principal Investigator: Byung Gun Lim, MD, PhD, Korea University Guro Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: April 10, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 2023GR0069

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