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NCT Number: NCT05841667

Impact of CES1 Genotype on 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.

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Key information

Conditions

Adult Elective Surgical Procedures Middle Aged

Age range

19 year–70 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Treatment and study plan

Remimazolam besylate

Drug

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.

Primary outcomes

  1. Dose-adjusted steady-state concentration of remimazolam

    Time frame: 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)

  2. Maintenance dose of remimazolam for maintaining general anesthesia

    Time frame: Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam

    Hourly maintenance dose of remimazolam for maintaining general anesthesia

  3. Total dose of remimazolam used to induce general anesthesia

    Time frame: 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 outcomes

  1. Time to LOC after remimazolam administration during anesthesia induction

    Time frame: Initiation of remimazolam administration ~ 5 minutes after start of remimazolam

    Determine the time to achieve LOC after remimazolam dosing.

  2. Time to bispectral index(BIS) < 60 after remimazolam administration during anesthesia induction

    Time frame: Initiation of remimazolam administration ~ 10 minutes after start of remimazolam

    Determine the time to achieve BIS <60 after remimazolam dosing

  3. Changes in BIS during induction and maintenance of anesthesia

    Time frame: Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam

    Measure BIS during anesthesia

  4. Percentage maintained BIS >60 during general anesthesia

    Time frame: Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration)

    Calculate "Time maintained BIS >60 / Time remimazolam administered"

  5. Changes in BIS during anesthesia induction and maintenance

    Time frame: Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam

    Assess BIS values during general anesthesia

  6. Postanesthesia care unit (PACU) length of stay

    Time frame: 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

  7. Emergence delirium

    Time frame: 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)

  8. Resedation

    Time frame: Immediately after extubation ~ 3 hours after PACU admission

    Richmond Agitation Sedation Scale (RASS) ≤-2 indicates resedation

  9. Precipitation

    Time frame: 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

  10. Injection pain caused by remimazolam administration

    Time frame: 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)

  11. Adverse events up to 48 hours after surgery

    Time frame: 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)

  12. 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)

    Time frame: 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)

  13. Total dose of remimazolam during general anesthesia

    Time frame: 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

  14. Total dose of remifentanil during general anesthesia

    Time frame: 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

  15. Operation time

    Time frame: Start of surgery ~ End of surgery(up to 10 hours after start of surgery)

    Determine how long the surgery was performed

  16. Anesthesia time

    Time frame: Initiation of remimazolam administration ~ Exit to the PACU (within 30 minutes after remimazolam cessation)

    Determine how long the general anesthesia was performed

  17. Flumazenil dosage

    Time frame: 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).

  18. Pain score in PACU

    Time frame: 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.

  19. Analgesic usage in PACU

    Time frame: 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.

  20. Delirium

    Time frame: After surgery ~ Hospital discharge (within 1 month after surgery)

    Determine delirium during post-operative hospitalization through electronic medical records

  21. Postoperative complications

    Time frame: After surgery ~ Hospital discharge (within 1 month after surgery)

    Identify any complications during post-operative hospitalization through electronic medical records

  22. Hospital stay after surgery

    Time frame: The day of surgery ~ Hospital discharge (within 1 month after surgery)

    Identify the hospital length of stay after surgery

Study contacts

Contact information is provided by the study sponsor or research team.

Byung Gun Lim, MD, PhD

CONTACT

[email protected]

82-2-2626-1437

Hye Bin Kim, MD, PhD

CONTACT

[email protected]

82-10-9183-5617

Sponsors and collaborators

Lead sponsor

Korea University Guro Hospital

Other

Registry information

Official study title

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

Important dates

Study start
2023
Primary completion
2025
Study completion
2025
First posted
May 3, 2023
Registry last updated
Oct 15, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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