Efficacy, Safety, and Pharmacokinetics of Sugammadex for Reversal of Neuromuscular Blockade (NMB) in Pediatric Participants (MK-8616-089)

Study Overview
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Brief Summary
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This trial will evaluate the efficacy, safety, and pharmacokinetics of sugammadex for the reversal of both moderate and deep neuromuscular blockade (NMB) induced by either rocuronium or vecuronium in pediatric participants. The primary efficacy hypothesis of this investigation is that sugammadex is superior to neostigmine in reversing moderate NMB in pediatric participants as measured by time to recovery to a train-of-four (TOF) ratio of ≥0.9.

Detailed Description
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This trial will be conducted in two parts: Part A and Part B. In Part A, pharmacokinetic (PK) sampling will be conducted to identify the pediatric dose providing sugammadex exposure similar to adults. For Part B participants, the efficacy of sugammadex (i.e. time to recovery of the TOF ratio) 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

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: Be categorized as American Society of Anesthesiologists (ASA) Physical Status Class 1, 2, or 3. Have a planned non-emergent surgical procedure or clinical situation (e.g., intubation) that requires moderate or deep NMB with either rocuronium or vecuronium. Have a planned surgical procedure or clinical situation that would allow objective neuromuscular monitoring techniques to be applied with access to the arm for neuromuscular transmission monitoring. Age between 2 to <17 years at Visit 2. If female, may participate if she is not pregnant, not breastfeeding, and at least one of the following: 1) Not a woman of childbearing potential (WOCBP); or 2) A WOCBP who agrees to follow the study contraceptive guidance during the treatment period and for at least 7 days after the last dose of study treatment. Exclusion Criteria: Has any clinically significant condition or situation (eg, anatomical malformation that complicates intubation) other than the condition being studied 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 (defined as estimated glomerular filtration rate (eGFR) <30 ml/min). 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. 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. Has been previously treated with sugammadex or has participated in a sugammadex clinical 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: 2 Years
Maximum Age: 16 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sugammadex 2 mg/kg (Part A)<br>Single intravenous (i.v.) bolus of sugammadex at 2 mg/kg. | Drug: Sugammadex 2 mg/kg<br>* For moderate NMB reversal, a single i.v. 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 TOF stimulations.<br>* Other names: BRIDION®;|
| Experimental: Sugammadex 4 mg/kg (Part A)<br>Single i.v. bolus of sugammadex at 4 mg/kg. | Drug: Sugammadex 4 mg/kg<br>* For deep NMB reversal, a single i.v. 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: BRIDION®;|
| Experimental: Sugammadex 2 mg/kg (Part B)<br>Single i.v. bolus of sugammadex at 2 mg/kg. | Drug: Sugammadex 2 mg/kg<br>* For moderate NMB reversal, a single i.v. 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 TOF stimulations.<br>* Other names: BRIDION®;|
| Experimental: Sugammadex 4 mg/kg (Part B)<br>Single i.v. bolus of sugammadex at 4 mg/kg. | Drug: Sugammadex 4 mg/kg<br>* For deep NMB reversal, a single i.v. 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: BRIDION®;|
| Active Comparator: Neostigmine (Part B)<br>Single i.v. 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 a second twitch (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 a second twitch (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 |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) From Dosing to Infinity (AUC0-∞) of Sugammadex [Part A] | The AUCo-∞ for sugammadex, defined as the area under the plasma concentration versus time plot, was determined in each Part A arm. | 2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose | 
| Plasma Clearance (CL) of Sugammadex [Part A] | The CL of sugammadex, defined as the rate of elimination relative to plasma concentration, was determined in each Part A arm. | 2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose | 
| Apparent Volume of Distribution (Vz) of Sugammadex [Part A] | The Vz of sugammadex, defined as the amount of drug administered relative to plasma concentrations, was determined in each Part A arm. | 2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose | 
| Maximum Plasma Concentration (Cmax) of Sugammadex [Part A] | The Cmax of sugammadex, defined as the maximum plasma concentration, was determined in each Part A arm. | 2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose | 
| Plasma Half-Life (t½) of Sugammadex [Part A] | The t½ of sugammadex, defined as the time required for the plasma concentration to decrease to 50% of maximum, was determined in each Part A arm. | 2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose | 
| Percentage of Participants With ≥1 Adverse Event (AE) [Parts A and B] | The percentage of participants with ≥1 AE(s) for up to 7 days after treatment was determined for each treatment group, pooled according to treatment received. An AE is defined as any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. | Up to 7 days | 
| Time to Recovery of Participant Train-of-Four (TOF) Ratio to ≥0.9 [Part B] | The time to recovery of TOF ratio to ≥0.9 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB. Per protocol, the efficacy analysis is based on comparison of the Part B: Sugammadex 2 mg arm versus the Part B: Neostigmine + (Glycopyrrolate or Atropine) arm. | Up to 30 minutes post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recovery of Participant TOF Ratio to ≥0.7 [Part B] | The time to recovery of TOF ratio to ≥0.7 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB. | Up to 30 minutes post-dose | 
| Time to Recovery of Participant TOF Ratio to ≥0.8 [Part B] | The time to recovery of TOF ratio to ≥0.8 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB. | Up to 30 minutes post-dose |