Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants Aged Birth to <2 Years (MK-8616-169)

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of sugammadex (MK-8616) for reversal of both moderate and deep neuromuscular blockade (NMB) in pediatric participants aged birth to <2 years. The primary hypothesis of this study is that sugammadex is superior to neostigmine in reversing moderate NMB as measured by time to neuromuscular recovery.

Detailed Description
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This trial will be conducted in two parts: Part A and Part B. In Part A, PK sampling will be conducted to identify the pediatric dose providing sugammadex exposure comparable to the next oldest age cohort. For Part B participants, the efficacy of sugammadex (i.e. neuromuscular recovery / time to extubation) will be assessed. Further, safety analyses will be conducted in both Parts A and B. Following completion of Part A, an interim analysis (IA) of the PK and safety data will be performed. Once the appropriate doses are confirmed and safety data is assessed for the 2 doses of sugammadex, then Part B will commence.

Official Title
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A Phase 4 Double-blinded, Randomized, Active Comparator-controlled Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants Aged Birth to <2 Years

Conditions
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Neuromuscular Blockade

Intervention / Treatment
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* Drug: Sugammadex 2 mg/kg
* Drug: Sugammadex 4 mg/kg
* Drug: Neostigmine + Glycopyrrolate
* Drug: Neostigmine + Atropine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Categorized as American Society of Anesthesiologists (ASA) Physical Status Class 1, 2, or 3. Has a planned non-emergent surgical procedure or clinical situation (e.g., intubation) that requires moderate or deep NMB with either rocuronium or vecuronium. Has a surgical procedure or clinical situation that would allow neuromuscular monitoring techniques to be applied for neuromuscular transmission monitoring. Is male or female, between birth and <2 years of age. Exclusion Criteria: Is a preterm infant or neonate <36 weeks gestational age at birth. Has any clinically significant condition or situation (e.g., anatomical malformation that complicates intubation) other than the condition requiring the use of NMBA that, in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in the trial. Has a neuromuscular disorder that may affect NMB and/or trial assessments. Is dialysis-dependent or has (or is suspected of having) severe renal insufficiency. Has or is suspected of having a family or personal history of malignant hyperthermia. Has or is suspected of having an allergy to study treatments or its/their excipients, to opioids/opiates, muscle relaxants or their excipients, or other medication(s) used during general anesthesia. Is expected to require mechanical ventilation after the procedure. Has received or is planned to receive toremifene and/or fusidic acid via IV administration within 24 hours before or within 24 hours after administration of study treatment. Use of medication expected to interfere with study treatments given in this trial. Has been previously treated with sugammadex or has participated in a sugammadex clinical trial within 30 days of signing the informed consent form of this current trial. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days of signing the informed consent/assent for this current trial.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 2 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A. Sugammadex 2 mg/kg<br>Single intravenous (IV) bolus of sugammadex at 2 mg/kg | Drug: Sugammadex 2 mg/kg<br>* For moderate NMB reversal, a single IV bolus of sugammadex (2 mg/kg) will be given after final dose of neuromuscular blocking agent (NMBA; rocuronium or vecuronium) and within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations.<br>* Other names: MK-8616;|
| Experimental: Part A. Sugammadex 4 mg/kg<br>Single IV bolus of sugammadex at 4 mg/kg. | Drug: Sugammadex 4 mg/kg<br>* For deep NMB reversal, a single IV bolus of sugammadex (4 mg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0).<br>* Other names: MK-8616;|
| Experimental: Part B. Sugammadex 2 mg/kg<br>Single IV bolus of sugammadex at 2 mg/kg. | Drug: Sugammadex 2 mg/kg<br>* For moderate NMB reversal, a single IV bolus of sugammadex (2 mg/kg) will be given after final dose of neuromuscular blocking agent (NMBA; rocuronium or vecuronium) and within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations.<br>* Other names: MK-8616;|
| Experimental: Part B. Sugammadex 4 mg/kg<br>Single IV bolus of sugammadex at 4 mg/kg. | Drug: Sugammadex 4 mg/kg<br>* For deep NMB reversal, a single IV bolus of sugammadex (4 mg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0).<br>* Other names: MK-8616;|
| Active Comparator: Part B. Neostigmine<br>Single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg). | Drug: Neostigmine + Glycopyrrolate<br>* For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as glycopyrrolate (10 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.<br>Drug: Neostigmine + Atropine<br>* For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as atropine (20 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A. Area Under the Plasma Concentration Time Curve (AUC) for Sugammadex | The AUC for sugammadex in plasma will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part A. Plasma Clearance (CL) of Sugammadex | The CL for sugammadex will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part A. Apparent Volume of Distribution (Vz) for Sugammadex | The Vz for sugammadex will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part A. Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | The Vss for sugammadex will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part A. Maximum Plasma Concentration (Cmax) of Sugammadex | The Cmax for sugammadex will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part A. Half-Life (t1/2) of Sugammadex in Plasma | The t1/2 for sugammadex will be calculated. | Baseline and 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | 
| Part B. Time to Neuromuscular Recovery | Time to neuromuscular recovery will be reported, defined as the interval from administration of reversal agent to time to neuromuscular recovery. | Within Day 1 | 
| Parts A and B. Adverse Events (AEs) | The number of participants experiencing an AE will be reported. | Up to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B. Time to Extubation | Time to extubation will be reported, defined as the interval from administration of reversal agent to removal of the endotracheal tube. | Within Day 1 |