Efficacy and Safety of Sevofran in Patients Scheduled for Elective Surgery Under General Anesthesia

Study Overview
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Brief Summary
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Sevoflurane is currently being used in more than 100 countries worldwide with an estimated 100 million operations having been performed using sevoflurane as a general anesthetic. After the expiry of the patent on sevoflurane as a pharmaceutical drug, a generic product (Sevofran®; Hana pharmacy, Co. Ltd, Seoul, Korea) has been launched. The aims of this study were to investigate the efficacy (mean minimum alveolar concentration), recovery characteristics (time to recovery of consciousness (ROC) and recovery, and BIS values at ROC and orientation), and safety (incidence and severity of adverse events) of generic sevoflurane in patients undergoing elective surgery.

Detailed Description
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Patients were randomly allocated to experimental group (generic sevoflurane) and active comparator group (original sevoflurane). Once in the operating room, patients were monitored with electrocardiography, non invasive blood pressure, pulse oximetry (Datex-Ohmeda S/5, Planar Systems, Inc., Beaverton, OR, USA) and BIS (Aspect 2000, Aspect Medical Systems, Inc., Newton, MA, USA). Anesthesia was induced with fentanyl (2 μg/kg) and propofol (2mg/kg). When patients were unconscious, original or generic sevoflurane was administered. Tracheal intubation was facilitated by administering rocuronium 0.6 mg/kg. The lungs of the patients were then ventilated with oxygen in air (1:2), and the ventilation rate was adjusted to maintain the end-tidal carbon dioxide partial pressure between 35 and 45 mmHg. The concentrations of carbon dioxide, sevoflurane, and oxygen were measured continuously using an infrared anesthetic gas analyzer (Datex-Ohmeda S/5, Planar Systems, Inc., Beaverton, OR, USA), which was calibrated before anesthesia for each patient using a standard gas mixture. The inspired concentration of sevoflurane was adjusted to maintain BIS values < 60 and stable haemodynamics (systolic arterial pressure (SAP) > 80 mmHg and heart rate (HR) > 45 beats/min). Also, it was titrated to prevent signs of inadequate anesthesia (sweating, facial flushing, movement and swallowing, HR > 90 beats/min without evidence of hypovolemia, and a 15 mmHg increase in SAP, compared with baseline SAP). Fentanyl 1 μg/kg was given if needed to resolve of signs of inadequate anesthesia. Concentration of compound A, formaldehyde, and methadone were measured at preset interval: 30, 60, 90, 120, 150, 180 min after administration of sevoflurane. Blood and urine samples were taken at preset interval for analyzing concentration of inorganic fluoride: 1 hr after administration of sevoflurane and every 2 hr during maintenance of anesthesia.

Official Title
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A Multi-center, Open-Label, Randomized, Active-controlled, Parallel, Phase 4 Clinical Trial to Assess the Efficacy and Safety of Sevofran in Patients Scheduled for Elective Surgery Under General Anesthesia

Conditions
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General Anesthesia, Sevoflurane, Generic Drugs

Intervention / Treatment
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* Drug: original sevoflurane
* Drug: generic sevoflurane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients scheduled for elective surgery under general anesthesia American Society Anesthesiologists Physical Status (ASA PS) 1 or 2 Aged 19 years or above Exclusion Criteria: ASA PS 3 or above aged under 19 years Contraindications against the use of sevoflurane Abnormal laboratory finding with clinical significance Evidence of pregnancy History of alcohol or drug abuse Hemoglobin < 11 mg/dl Neurological or psychiatric disease Unable or unwilling to give informed consent

Ages Eligible for Study
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Minimum Age: 19 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: generic sevoflurane<br> | Drug: generic sevoflurane<br>* Sevoflurane content: 99.99%, compound A: 3.8 ppm, water content (sample was opened, sealed and stored for 2 weeks) : 0.044% w/v<br>* Other names: Sevofran® (Hana Pharmacy, Co. Ltd, Seoul, Korea);|
| Active Comparator: origianl sevoflurane<br> | Drug: original sevoflurane<br>* Sevoflurane content: 99.9985%, compound A: 4.6 ppm, water content (sample was opened, sealed and stored for 2 weeks): 0.072% w/v<br>* Other names: Sevorane® (Abott Korea Ltd, Seoul, Korea);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of mean minimum alveolar concentration between original and generic sevoflurane | Minimum alveolar concentration was determined by end-tidal sevoflurane concentrations. Mean MAC was calculated as following equation, Mean MAC = (MAC * hour) / (maintenance time from administration of hypnotic agent (propofol) for acquring loss of consciousness to extubation) | During mainenance of anesthesia under general anesthesia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of secondary efficacy and safety endpoints between two inhalation agents | Secondary efficacy and safety characteristics include following items. Anesthesia exposure: MAC * hour [Time frame: maintenanane period of anesthesia] Bispectral index, BIS [Time frame: time to recovery of consciousnessn, time to recovery of orientation] Adverse event [Time frame: maintenanane period of anesthesia] Incidence and severity of postopertive nausea and vomiting [Time frame: 24 hours postoperatively] Concentrations of compound A, formaldehyde, methanol [Time frame: 30, 60, 90, 120, 150, 180 min after sevoflurane administration] | During maintenance of anesthesia under general anesthesia | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, Minimum alveolar concentration, Safety, Sevoflurane