Comparison of Sugammadex (MK-8616/Org 25969) With Neostigmine Administered at 1-2 Post-tetanic Counts (PTCs) After Administration of Rocuronium or Vecuronium (19.4.302/P05945/MK-8616-025)

Study Overview
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Brief Summary
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The purpose of the trial is to demonstrate a faster recovery from neuromuscular block (NMB) induced with rocuronium or vecuronium after reversal by 4.0 mg/kg of Org 25969 compared with reversal by 70 μg/kg of neostigmine in combination with 14 μg/kg glycopyrrolate.

Official Title
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A Multicenter, Randomized, Parallel Group Comparative, Active-Controlled, Safety-assessor Blinded. Phase IIIa, Pivotal Trial in Adult Subjects Comparing Org 25969 With Neostigmine as Reversal Agent of a Neuromuscular Block Induced by Maintenance Dosing of Rocuronium or Vecuronium at 1-2 PTCs

Conditions
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Anesthesia, General

Intervention / Treatment
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* Drug: sugammadex
* Drug: neostigmine
* Drug: vecuronium
* Drug: rocuronium
* Drug: glycopyrrolate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists (ASA) Class 1 to 4 18 years or older Scheduled to undergo an elective surgical procedure under general anesthesia requiring the use of rocuronium or vecuronium for endotracheal intubation and maintenance of neuromuscular block Scheduled for surgery in supine position Given written informed consent Exclusion Criteria: Participants in whom a difficult intubation is expected due to anatomical malformations Known or suspected to have neuromuscular disorders impairing neuromuscular blockade and/or significant renal dysfunction Known or suspected to have a (family) history of malignant hyperthermia Known or suspected to have an allergy to narcotics, muscle relaxants, or other medications used during surgery Receiving medication known to interfere with neuromuscular blocking agents such as anticonvulsants, antibiotics, and magnesium (Mg2+) Participants in whom the use of neostigmine and/or glycopyrrolate may be contraindicated Female participants who are pregnant or breast-feeding Females participants of childbearing potential not using an acceptable method of birth control [condom or diaphragm with spermicide, vasectomized partner (> 6 months), IUD, abstinence] Participants who had already participated in an Org 25969 trial Participants who had participated in another clinical trial, not pre-approved by Organon, within 30 days of entering into Protocol 19.4.302

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 |
| --- | --- |
| Experimental: rocuronium+sugammadex<br>Participants received a single bolus dose of 0.60 mg/kg rocuronium prior to intubation. The neuromuscular block was maintained with 0.15 mg/kg rocuronium if needed. At 1-2 post-tetanic counts (PTC) and after the last dose of rocuronium, a single bolus dose of 4.0 mg/kg sugammadex was administered. | Drug: sugammadex<br>* Administered as an intravenous (IV) infusion<br>* Other names: BRIDION®;Drug: rocuronium<br>* Administered as an IV infusion<br>* Other names: ZEMURON®;|
| Active Comparator: rocuronium+neostigmine<br>Participants received a single bolus dose of 0.60 mg/kg rocuronium prior to intubation. The neuromuscular block was maintained with 0.15 mg/kg rocuronium if needed. At 1-2 PTC and after the last dose of rocuronium, a single bolus dose of 70.0 μg/kg neostigmine (up to a maximum dose of 5 mg) was administered in combination with 14.0 μg/kg glycopyrrolate. | Drug: neostigmine<br>* Administered as an IV infusion<br>* Other names: PROSTIGMIN®;Drug: rocuronium<br>* Administered as an IV infusion<br>* Other names: ZEMURON®;Drug: glycopyrrolate<br>* Administered as an IV infusion<br>* Other names: ROBINUL®;|
| Experimental: vecuronium+sugammadex<br>Participants received a single bolus dose of 0.1 mg/kg vecuronium prior to intubation. The neuromuscular block was maintained with 0.015 mg/kg vecuronium if needed. At 1-2 PTC and after the last dose of vecuronium, a single bolus dose of 4.0 mg/kg sugammadex was administered. | Drug: sugammadex<br>* Administered as an intravenous (IV) infusion<br>* Other names: BRIDION®;Drug: vecuronium<br>* Administered as an IV infusion<br>* Other names: NORCURON®;|
| Active Comparator: vecuronium+neostigmine<br>Participants received a single bolus dose of 0.1 mg/kg vecuronium prior to intubation. The neuromuscular block was maintained with 0.015 mg/kg vecuronium if needed. At 1-2 PTC and after the last dose of vecuronium, a single bolus dose of 70.0 μg/kg neostigmine (up to a maximum dose of 5 mg) was administered in combination with 14.0 μg/kg glycopyrrolate. | Drug: neostigmine<br>* Administered as an IV infusion<br>* Other names: PROSTIGMIN®;Drug: vecuronium<br>* Administered as an IV infusion<br>* Other names: NORCURON®;Drug: glycopyrrolate<br>* Administered as an IV infusion<br>* Other names: ROBINUL®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.9 After Neuromuscular Block (NMB) Induced by Rocuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.9 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.9 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 3 hours after administration of study drug | 
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.9 After Neuromuscular Block (NMB) Induced by Vecuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.9 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.9 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 6 hours after administration of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.7 After Neuromuscular Block (NMB) Induced by Rocuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.7 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.7. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.7 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 2 hours after administration of study drug | 
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.7 After Neuromuscular Block (NMB) Induced by Vecuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.7 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.7. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.7 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 4 hours after administration of study drug | 
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.8 After Neuromuscular Block (NMB) Induced by Rocuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.8 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.8. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.8 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 3 hours after administration of study drug | 
| Time From Start of Administration of Sugammadex or Neostigmine to Recovery of the T4/T1 Ratio to 0.8 After Neuromuscular Block (NMB) Induced by Vecuronium | Mean time from start of sugammadex or neostigmine administration to recovery of T4/T1 ratio to 0.8 was assessed by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.8. The greater the T4/T1 ratio represented the greater the recovery from NMB; with a value of 0.0 representing no recovery and 1.0 representing full recovery. Reduced recovery time of the T4/T1 ratio to 0.8 indicated faster recovery from NMB. Mean time was collected in minutes and seconds but converted to and presented in minutes only. The analysis included a procedure for the imputation of missing recovery times. | Up to approximately 5 hours after administration of study drug | 
| Number of Participants Awake and Oriented After Anesthesia (Clinical Assessment of Level of Consciousness) | The number of participants who were awake and oriented was assessed as part of an overall assessment of the clinical level of consciousness by the investigator. The clinical level of consciousness was used as a measure of recovery from NMB at 2 timepoints: prior to transfer to the recovery room after extubation and prior to discharge from the recovery room. Attempts were made to arouse participants every 15 minutes with mild prodding, mild shaking, and asking questions regarding name, location, and day of the week. The assessment ended once the participant was awake and fully orientated, 24 hours, or discharged from the hospital if discharge occurs before 24 hours; whichever occurred first. Participants were given a level of consciousness based on what type of stimulation they responded to. Participants who were not cooperative with the examination were not included in the assessment. | Up to 24 hours | 
| Number of Participants Aroused With Minimal Stimulation After Anesthesia (Clinical Assessment of Level of Consciousness) | The number of participants aroused with minimal stimulation was assessed as part of an overall assessment of the clinical level of consciousness by the investigator. The clinical level of consciousness was used as a measure of recovery from NMB at 2 timepoints: prior to transfer to the recovery room after extubation and prior to discharge from the recovery room. Attempts were made to arouse participants every 15 minutes with mild prodding, mild shaking, and asking questions regarding name, location, and day of the week. The assessment ended once the participant was awake and fully orientated, 24 hours, or discharged from the hospital if discharge occurs before 24 hours; whichever occurred first. Participants were given a level of consciousness based on what type of stimulation they responded to. Participants who were not cooperative with the examination were not included in the assessment. | Up to 24 hours | 
| Number of Participants Responsive Only to Tactile Stimulation After Anesthesia (Clinical Assessment of Level of Consciousness) | The number of participants responsive only to tactile stimulation was assessed as part of an overall assessment of the clinical level of consciousness by the investigator. The clinical level of consciousness was used as a measure of recovery from NMB at 2 timepoints: prior to transfer to the recovery room after extubation and prior to discharge from the recovery room. Attempts were made to arouse participants every 15 minutes with mild prodding, mild shaking, and asking questions regarding name, location, and day of the week. The assessment ended once the participant was awake and fully orientated, 24 hours, or discharged from the hospital if discharge occurs before 24 hours; whichever occurred first. Participants were given a level of consciousness based on what type of stimulation they responded to. Participants who were not cooperative with the examination were not included in the assessment. | Up to 24 hours | 
| Number of Participants Able to Perform a 5-second Head Lift | The number of participants who were able to lift their head for 5 seconds was assessed by the investigator as a measure of recovery from NMB at 2 timepoints: prior to transfer to the recovery room after extubation and prior to discharge from the recovery room. The assessment was performed every 15 minutes until the first successful 5-second head lift was achieved. Participants who were not cooperative with the examination were not included in the assessment. | Up to 24 hours | 
| Number of Participants Experiencing General Muscle Weakness | The number of participants experiencing general muscle weakness was assessed by the investigator as a measure of recovery from NMB at 2 timepoints: prior to transfer to the recovery room after extubation and prior to discharge from the recovery room. The assessments were performed every 15 minutes until the absence of general muscle weakness. A standardized examination form was used to determine the presence or absence of muscle weakness in various muscle groups. Participants who were not cooperative with the examination were not included in the assessment. | Up to 24 hours |