Efficacy and Safety of Remimazolam (CNS7056) Compared to Propofol for Intravenous Anesthesia During Elective Surgery

May 27, 2020 updated by: Paion UK Ltd.

Phase III Confirmatory Efficacy and Safety Trial of Remimazolam (CNS7056) Compared With Propofol for Intravenous Anesthesia During Elective Surgery in ASA Class III/IV Patients

A phase III confirmatory trial evaluating the efficacy and safety of remimazolam (CNS7056) compared to propofol for intravenous anesthesia during elective surgery in ASA Class III/IV patients.

Study Overview

Status

Completed

Intervention / Treatment

Detailed Description

This is a Phase III single-blind, randomized, controlled, non-inferiority multi-center trial in American Society of Anesthesiologists (ASA) Class III/IV patients undergoing elective surgery, comparing remimazolam to propofol for induction and maintenance of intravenous anesthesia. In accordance with general anesthetic standard regimen, remimazolam or propofol, will be administered together with remifentanil as analgesic agent, and with a neuromuscular blocker to facilitate intubation and achieve muscle relaxation

Study Type

Interventional

Enrollment (Actual)

469

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Bavaria
      • Erlangen, Bavaria, Germany, 91054
        • University of Erlangen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria

  • Male or female ASA III/IV patients at least 18 years old, scheduled for an elective surgical procedure of a minimum duration of approximately 90 minutes under general anesthesia (GA) and planned to be extubated immediately post-operatively.
  • Total intravenous GA with the requirement for mechanical ventilation via endotracheal tube and necessary invasive blood pressure (BP) monitoring either due to severity of illness, severity of concomitant diseases, type of surgery or decisions of the anesthesia staff.
  • Patients scheduled to stay in the hospital long enough after the surgical procedure to perform all trial follow-up procedures (~1 day)
  • For female patients of childbearing potential: Negative result of a pregnancy test taken shortly before the start of the administration of the IMP as well as consent to use highly effective birth control from the last menstrual cycle prior to the start of the IMP until the end of the trial follow-up procedures. Highly effective methods of birth control include:

    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal and transdermal
    • Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable and implantable
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomised partner (provided that the partner is the sole sexual partner of the female patient of childbearing potential and that the vasectomised partner has received medical assessment of the surgical success)
    • Sexual abstinence (this method is not acceptable in Switzerland)

Women who had their last menstruation at least two years ago or who underwent surgical interventions (surgical birth control, bilateral oophorectomy, hysterectomy, etc.) are regarded as having no childbearing potential

Exclusion criteria

  • Patients scheduled for spinal anesthesia, epidural anesthesia (central neuraxial anesthesia) or regional anesthesia. The placement of a peridural catheter with a test dose application of a local anesthetic drug (up to 5 mL) to verify correct positioning to achieve post-operative analgesia and the regional administration of local anesthetic for post-operative analgesia after wound closure is accepted.
  • Patients undergoing transplant surgery, cardiac surgery, or intracranial neurosurgery, patients which have to be in prone position for surgery, emergency surgery, or any surgical procedure with the need for or scheduled for post-operative ventilator support.
  • Patients undergoing surgical procedures that require keeping the BP at a high level, e.g. surgical procedures in beach chair position
  • Patients with severe hypertension, i.e., one baseline result of systolic BP 200 mmHg or more and / or diastolic BP of 120 mmHg or more. Baseline is defined as the time after signature of the informed consent form (ICF) and before arrival in the operating room (OR) suite.
  • Patients with total bilirubin of ≥3.0 mg/dL or ≥3 times increase in aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) than the institutional reference range in laboratory tests, or any other laboratory results that make the patient unsuitable for the trial. All laboratory tests relevant for subject's enrolment must be performed within 7 days prior to start of IMP*

    * If the screening samples for the central laboratory were taken earlier than within the last 7 days prior to start of IMP, the lab parameters relevant for subject's enrolment are to be determined in a local laboratory within 7 days prior to start of IMP. If results from samples taken within 7 days prior to the start of the IMP/the surgery from a local laboratory are available, these can be used. If no results from the last 7 days prior to the start of the IMP/the surgery are available, samples need to be taken for the purpose of this trial and to be analysed in a local laboratory.

  • Patients with end stage renal disease (ESRD) requiring scheduled dialysis
  • Patients with known anaphylactic reactions to benzodiazepines, propofol, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), dextran, neuromuscular blocking agents, flumazenil, naloxone, or other anesthetic agents, or a medical condition such that these agents are contraindicated (according to local label)
  • Presence of acute alcoholic or illicit drug intoxication, shock or coma state
  • Known current dependency from central nervous system depressant drugs or alcohol
  • Patients with gastroparesis or delayed gastric emptying, gastric reflux or any other increased risk for gastric aspiration
  • Patients with an anticipated (small mouth opening, impaired neck movement, goitre, head and neck tumours or any other anatomical reason) or known airway difficulties or with known difficulties in airway maintenance or mask ventilation
  • Patients in whom Narcotrend (NCT) may not provide reliable results due to organic defect of the brain or forehead, or any neurologic disease interfering with the EEG monitoring
  • Patients on treatment with valproate
  • Any pregnant or breast-feeding patient
  • Patients who participated in any clinical trial within 30 days or 5 times the half-life of the drug under investigation, whichever is longer, prior to the beginning of administration of the IMP. Exception: Non-interventional trials as defined in the European Clinical Trials Directive 2001/20/EC: A trial where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods should be used for the analysis of the collected data.
  • Any patient judged to lack the ability to give informed consent or perform the trial assessments (e.g., due to dementia)
  • Any patient judged by the Principal Investigator (PI) or Sub-Investigator to be inappropriate for the subject for any other reason

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intravenous Remimazolam 50 mg

For induction of general anesthesia, remimazolam is co-administered with remifentanil for analgesia and with a muscle relaxant as necessary.

For maintenance of general anesthesia remimazolam is titrated to effect. Administration of boluses of remimazolam is allowed. Remifentanil is continued and/or titrated. Boluses of muscle relaxants are given throughout the surgical procedure as needed.

For induction and maintenance of general anesthesia
Active Comparator: Intravenous Propofol 2%

For induction of general anesthesia, propofol is co-administered with remifentanil for analgesia and with a muscle relaxant as necessary.

For maintenance of general anesthesia propofol is titrated to effect. Administration of boluses of propofol is allowed. Remifentanil is continued and/or titrated. Boluses of muscle relaxants are given throughout the surgical procedure as needed.

For induction and maintenance of general anesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage (%) of time of Narcotrend Index (NCI) values ≤ 60 during maintenance phase of general anesthesia (defined as time between the first skin incision and the completion of the last skin suture)
Time Frame: maintenance phase of general anesthesia (time between the first skin incision and the completion of the last skin suture)
The primary efficacy endpoint (PEP) is the anesthetic effect of remimazolam and propofol assessed as percent (%) of time of NCI ≤60 during the maintenance phase of general anesthesia
maintenance phase of general anesthesia (time between the first skin incision and the completion of the last skin suture)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of events of critical decrease(s) in mean arterial blood pressure (MAP)
Time Frame: From start of Investigational Medicinal Product (IMP) administration until 15 minutes after first skin incision

For this endpoint, each event from the following categories will be counted and summed up per patient:

  • Incidence of MAP dropping below 65 mmHg for at least 1 minute duration
  • Incidence of a MAP decrease of more than 20% below the calculated (mean) baseline MAP value for at least 1 minute duration
  • Incidence of a MAP decrease of more than 30% below the calculated (mean) baseline MAP value for at least 1 minute duration
  • Number of norepinephrine boluses (0.01 mg) required or, if an infusion is used to maintain MAP equal to or above 65 mmHg, then each time interval of 2 minutes duration of continuous norepinephrine infusion will be counted as one event.
From start of Investigational Medicinal Product (IMP) administration until 15 minutes after first skin incision

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of time of NCI ≤60 and ≥40 during the maintenance phase
Time Frame: During the maintenance phase of general anesthesia: from first skin incision to last skin suture
Adherence to a pre-defined corridor to avoid sedation being too light or being too deep
During the maintenance phase of general anesthesia: from first skin incision to last skin suture
Time from start of IMP administration to loss of consciousness
Time Frame: During induction of general anesthesia
Loss of consciousness is defined as modified observer's assessment of alertness / sedation = 0
During induction of general anesthesia
Time from stop of IMP to end of extubation
Time Frame: During recovery phase of general anesthesia
Extubation is defined as the precise time (hh:mm) by when the tracheal tube used for the mechanical ventilation is removed
During recovery phase of general anesthesia
Time from stop of IMP to Modified Aldrete Score = 10
Time Frame: During recovery phase of general anesthesia
The time by when full recovery is reached defined as the time by when the Modified Aldrete Score is 10 for the first time
During recovery phase of general anesthesia
Delirium assessed by the Nursing Delirium Screening Scale (Nu-DESC)
Time Frame: During Screening, shortly before starting IMP (in the preparation period), in the Recovery Period and during Follow-up (up to 1 week after the end of the surgery)
Any appearance of symptoms indicating delirium will be captured using the Nu-DESC
During Screening, shortly before starting IMP (in the preparation period), in the Recovery Period and during Follow-up (up to 1 week after the end of the surgery)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: Jörg Fechner, Prof. Dr., University Erlangen-Nürnberg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 24, 2018

Primary Completion (Actual)

April 2, 2020

Study Completion (Actual)

April 2, 2020

Study Registration Dates

First Submitted

September 3, 2018

First Submitted That Met QC Criteria

September 6, 2018

First Posted (Actual)

September 7, 2018

Study Record Updates

Last Update Posted (Actual)

May 28, 2020

Last Update Submitted That Met QC Criteria

May 27, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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