Efficacy, Safety and Pharmacokinetics of Sugammadex (Org 25969; MK-8616) at 3 Different Time Points After 0.6 mg/kg Esmeron® in Male Participants (P05940; MK-8616-020).

Study Overview
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Brief Summary
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This study investigates the efficacy, safety, and pharmacokinetics of sugammadex (Org 25969; MK-8616) when administered for the reversal of neuromuscular blockade in male participants receiving surgery, classified as American Society of Anesthesiologists (ASA) class 1 (otherwise normal, healthy participant) to class 2 (participant with mild systemic disease). The primary objective of this study is to explore the dose-response relation of sugammadex given as a reversal agent at 3, 5, or 15 minutes following administration of 0.6 mg/kg Esmeron®.

Official Title
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A Multi-center, Randomized, Assessor-blinded, Placebo Controlled, Phase II, Parallel Dose-finding Trial in Male Subjects of ASA 1-2 to Assess the Efficacy, Safety and Pharmacokinetics of 5 Doses of Org 25969 When Administered After 0.6 mg.Kg-1 Esmeron® at 3, 5 or 15 Minutes

Conditions
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Neuromuscular Blockade

Intervention / Treatment
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* Drug: Placebo
* Drug: Sugammadex
* Drug: Esmeron®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants of ASA class 1 to 2. Participants scheduled for surgical procedures with an anticipated duration of anesthesia of at least 75 minutes, without further need for muscle relaxation other than for intubation. Exclusion Criteria: Participants in whom a difficult intubation because of anatomical malformations is expected. Participants known or suspected to have neuromuscular disorders and/or significant hepatic or renal dysfunction. Participants known or suspected to have a (family) history of malignant hyperthermia. Participants known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia. Participants receiving medication known to interfere with neuromuscular blocking agents such as anticonvulsants, aminoglycosides, and Mg^2+. Participants who have already participated in this trial. Participants who have participated in another clinical trial, not pre-approved by NV Organon, within 30 days of entering into this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Male

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm A. Placebo; given 3 minutes after Esmeron®<br>Placebo (single intravenous (IV) bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Placebo<br>* 0.9% NaCl administered as a fast IV bolus dose (within 30 seconds).<br>Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm B. 1 mg/kg Sugammadex; given 3 minutes after Esmeron®<br>Sugammadex (1 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm C. 2 mg/kg Sugammadex; given 3 minutes after Esmeron®<br>Sugammadex (2 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm D. 4 mg/kg Sugammadex; given 3 minutes after Esmeron®<br>Sugammadex (4 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm E. 6 mg/kg Sugammadex; given 3 minutes after Esmeron®<br>Sugammadex (6 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm F. 8 mg/kg Sugammadex; given 3 minutes after Esmeron®<br>Sugammadex (8 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Placebo Comparator: Arm G. Placebo; given 5 minutes after Esmeron®<br>Placebo (single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Placebo<br>* 0.9% NaCl administered as a fast IV bolus dose (within 30 seconds).<br>Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm H. 1 mg/kg Sugammadex; given 5 minutes after Esmeron®<br>Sugammadex (1 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm I. 2 mg/kg Sugammadex; given 5 minutes after Esmeron®<br>Sugammadex (2 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm J. 4 mg/kg Sugammadex; given 5 minutes after Esmeron®<br>Sugammadex (4 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm K. 6 mg/kg Sugammadex; given 5 minutes after Esmeron®<br>Sugammadex (6 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm L. 8 mg/kg Sugammadex; given 5 minutes after Esmeron®<br>Sugammadex (8 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Placebo Comparator: Arm M. Placebo; given 15 minutes after Esmeron®<br>Placebo (single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Placebo<br>* 0.9% NaCl administered as a fast IV bolus dose (within 30 seconds).<br>Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm N. 1 mg/kg Sugammadex; given 15 minutes after Esmeron®<br>Sugammadex (1 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm O. 2 mg/kg Sugammadex; given 15 minutes after Esmeron®<br>Sugammadex (2 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm P. 4 mg/kg Sugammadex; given 15 minutes after Esmeron®<br>Sugammadex (4 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm Q. 6 mg/kg Sugammadex; given 15 minutes after Esmeron®<br>Sugammadex (6 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: Arm R. 8 mg/kg Sugammadex; given 15 minutes after Esmeron®<br>Sugammadex (8 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®. | Drug: Sugammadex<br>* Sugammadex administered as a fast IV bolus dose (within 30 seconds), dosed according to participant actual body weight.<br>* Other names: Org 25969; MK-8616; Bridion®.;Drug: Esmeron®<br>* Esmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.<br>* Other names: Rocuronium bromide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time From Start of Study Treatment Administration to Recovery of the T4/T1 Ratio to 0.9 | Mean time from start of study treatment administration to recovery of participant T4/T1 ratio to 0.9 was assessed through the repeated application (every 15 seconds) of an electrical stimulation protocol. Specifically, 4 electrical stimulations were applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) was assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio indicates the current degree of neuromuscular blockade (NMB) present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Further, reduced recovery time of the T4/T1 ratio to 0.9 indicates faster recovery from NMB. Summary data, originally presented in the format of units minutes:seconds (mm:ss), was reformatted to be presented in the single unit of minutes (min). | Up to 70 minutes following administration of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Heart Rate at Baseline | Mean heart rate at baseline was assessed. Baseline heart rate was defined as the heart rate measured under stable anesthesia prior to administration of study treatment. | Up to 45 minutes prior to study treatment administration | 
| Mean Heart Rate at 2 Minutes Following Administration of Study Treatment | Mean heart rate at 2 minutes following administration of study treatment was assessed. | 2 minutes following administration of study treatment | 
| Mean Heart Rate at 30 Minutes Following Administration of Study Treatment | Mean heart rate at 30 minutes following administration of study treatment was assessed. | 30 minutes following administration of study treatment | 
| Mean Corrected QT Interval (QTc) at Baseline | Mean QTc interval at baseline was assessed. Baseline QTc interval was defined as the QTc interval measured under stable anesthesia prior to administration of study treatment. The baseline QTc interval is corrected for participant heart rate at baseline prior to study treatment administration using Fridericia's correction, where QTc = QT interval/(RR interval)^(1/3). RR interval = 60/heart rate. | Up to 45 minutes prior to study treatment administration | 
| Mean Corrected QT Interval (QTc) at 2 Minutes Following Administration of Study Treatment | Mean QTc interval at 2 minutes following administration of study treatment was assessed. The QTc interval is corrected for participant heart rate at 2 minutes following study treatment administration using Fridericia's correction, where QTc = QT interval/(RR interval)^(1/3). RR interval = 60/heart rate. | 2 minutes following administration of study treatment | 
| Mean Corrected QT Interval (QTc) at 30 Minutes Following Administration of Study Treatment | Mean QTc interval at 30 minutes following administration of study treatment was assessed. The QTc interval is corrected for participant heart rate at 30 minutes following study treatment administration using Fridericia's correction, where QTc = QT interval/(RR interval)^(1/3). RR interval = 60/heart rate. | 30 minutes following administration of study treatment | 
| Number of Participants Experiencing an Adverse Event | The number of participants experiencing an adverse event (AE) was assessed. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. | Up to 7 days following administration of study treatment |