Study of the Efficacy and Safety of Remimazolam in General Anesthesia in Adults Undergoing Cardiac Surgery

Study Overview
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Brief Summary
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This study investigates the use of remimazolam as a sedative/hypnotic in general anesthesia. Remimazolam or propofol will be administered together with fentanyl/sufentanil/remifentanil as opioid analgesics and a neuromuscular blocker. In total, 530 patients will be randomized. This group of 530 patients will be split randomly into 2 groups as follows: • 106 patients will be randomized to induction with propofol plus fentanyl or sufentanil or remifentanil and a neuromuscular blocker. Throughout maintenance, the patients will receive propofol and remifentanil until weaning from the mechanical ventilation on the ICU or PACU within 24 hours after induction. Afterwards, sedation with propofol as study medication has to be ended. If necessary, the sedation is to be continued with the hospital's own supplies (propofol or other sedative). • 424 patients will be randomized to induction with remimazolam 6.0 mg/kg/hr together with fentanyl or sufentanil or remifentanil and a neuromuscular blocker. Throughout maintenance, the patients will receive remimazolam and remifentanil until weaning from the mechanical ventilation on the ICU or PACU within 24 hours after induction. The primary endpoint is successful sedation is defined as a Narcotrend index of 60 or less during at least 85% of the maintenance time and no rescue sedative medication administered. The maintenance starts at arrival at the operation theater and ends with the completion of the last skin suture.

Official Title
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A Randomized, Single-blind, Propofol-controlled Phase III Study Evaluating the Efficacy and Safety of Remimazolam in GA in Adult Patients Undergoing Cardiac Surgery, Including Follow-up Sedation in the Post-anesthesia Care Unit/ICU

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Propofol
* Drug: Remimazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for major non-emergency cardiac surgery, i.e. surgery assumed to require more than 2 hours of maintenance of general anesthesia and to require the use of extracorporeal circulation, including coronary bypass(es), valve replacement(s), and associated procedures and on-pump minimal invasive surgery Scheduled to receive mechanical ventilation via tracheal intubation (oropharyngeal or nasotracheal) Age at least 18 years Body mass index 18 to ≤40 kg/m2 Willingness and ability to give informed consent, to understand, participate and comply with all study requirements For women of childbearing potential: negative pregnancy test (serum or urine strip) as well as using a highly effective method of birth control. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, with the following routes of administration: oral, intravaginal, transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation, with the following routes of administration: oral, injectable, implantable Intrauterine device Intrauterine hormone-releasing system Bilateral tubal occlusion Sexual abstinence A woman was considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods included hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Exclusion Criteria: Re-do cardiac surgery Surgical procedures that comprised the use of drugs and/or devices that were not approved for marketing Severe tricuspidal insufficiency (III grade) Planned cooling of the patient's body below 32ºC History of or planned stop of circulation, e.g. due to repair of type A dissection of aorta or removal of thrombi from pulmonary artery Planned to receive epidural/spinal anesthesia together with general anesthesia Evidence of uncontrolled hepatic, central nervous system, respiratory, or metabolic dysfunction, or other clinically significant findings at screening that, in the investigator's or medical monitor's opinion, excluded patients from the study Poorly controlled hypertension (e.g. systolic blood pressure ≥160 mmHg under antihypertensive medication at screening) Patients with severe renal insufficiency or end-stage renal disease (creatinine clearance below 30 mL/min or estimated glomerular filtration rate below 30 mL/min/1.73 m2). Measuring only one of both parameters was sufficient to assess the eligibility of a patient. Patients with clinically uncontrolled coagulation abnormalities, or with coagulation abnormalities not under adequate treatment Patients scheduled for heart or lung transplantation Patients with infectious cardiac disorders (e.g. endocarditis, myocarditis) Patients with sepsis Emergency surgery, status of shock or coma Patients with an ejection fraction from the left ventricle of less than 20% Patients with acute right heart failure Pre-operative use of phosphodiesterase 3 inhibitors Patients with a history of resuscitation Known resistance to benzodiazepines or history of paradoxical effects after administration of benzodiazepines History of hypersensitivity to benzodiazepines, propofol, remifentanil hydrochloride, neuromuscular blockers, flumazenil or other anesthetic agents Use of benzodiazepines within 5 times their half-life or 5 times the half-life of their active metabolites. Exception: Pre-medication with a benzodiazepine according to local standards was allowed. Epilepsy Myasthenia gravis or myasthenic syndrome History of any severe allergy defined as urticaria, angioedema or anaphylaxis Dependence from drugs or history of drug abuse Dependence from alcohol or history of alcohol abuse within the last 5 years Acute alcoholic intoxication or ethanol intake within 48 hours prior to surgery Acute narrow-angle glaucoma Female patients of childbearing potential without acceptable method of birth control (for definitions: see inclusion criterion 6). Pregnant or breast-feeding female patients Patients in receipt of any investigational drug within 30 days or less than 7 half-lives (whichever was longer) before the start of the study, or scheduled to receive one during the study period. Administration of remimazolam in the past Patients unable to communicate with the investigator as required for the study Other reasons that, according to the investigator, excluded the patient from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Propofol<br>Propofol for induction will be given as a bolus administered manually at 2.0-2.5 mg/kg slowly over approximately 1 minute. Immediately after the propofol bolus for induction has been given, propofol maintenance will be started at a dose of 3.0-9.0 mg/kg/hr and adjusted as needed. | Drug: Propofol<br>* Hypnotic drug used for anesthesia<br>* Other names: Diprivan;|
| Experimental: Remimazolam<br>Remimazolam for induction will be given at 6.0 mg/kg/hr, which can be increased to 12.0 mg/kg/hr for one minute if loss of consciousness is not reached after 3 minutes. Immediately after the remimazolam dose for induction has been given, remimazolam maintenance will be given at 1.0 mg/kg/hr and adjusted by down-titration or up-titration to a maximum of 3.0 mg/kg/hr. | Drug: Remimazolam<br>* Benzodiazepine being developed for sedation and anesthesia.<br>* Other names: CNS7056;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of Procedure | A narcotrend index of 60 or less during at least 85% of the maintenance time and no rescue sedative medication administered. | During maintenance phase of operation - between arrival at operation theatre and completion of last skin suture (estimated up to 24 hours). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamic stability | Expressed as the amount of norepinephrine used. | From the start of study medication until completion of the last skin suture (estimated up to 24 hours). |