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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
288
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.
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).
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.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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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.
Childrens Hospital Los Angeles ( Site 0030)
Los Angeles, California, United States
Lucille Packard Children's Hospital ( Site 0006)
Palo Alto, California, United States
Rady Children's Hospital-San Diego ( Site 0035)
San Diego, California, United States
Children's National Medical Center ( Site 0008)
Washington D.C., District of Columbia, United States
C.S. Mott Children's Hospital/ University of Michigan Medical center ( Site 0014)
Ann Arbor, Michigan, United States
Saint Peter's University Hospital [New Brunswick, NJ] ( Site 0009)
New Brunswick, New Jersey, United States
Duke University Medical Center ( Site 0019)
Durham, North Carolina, United States
The Children's Hospital of Philadelphia ( Site 0015)
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC ( Site 0005)
Pittsburgh, Pennsylvania, United States
Memorial Hermann Medical Center University of Texas Medical School ( Site 0038)
Houston, Texas, United States
...and 20 more locations
Time frame: 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.
Time frame: Up to 30 minutes post-dose
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.
Time frame: 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.
Time frame: Up to 30 minutes post-dose