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

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

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.

Study Overview

• Status: Completed
• Conditions: Neuromuscular Blockade
• Intervention / Treatment: Drug: Sugammadex 2 mg/kg; Drug: Sugammadex 4 mg/kg; Drug: Neostigmine + Glycopyrrolate; Drug: Neostigmine + Atropine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@merck.com

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • The Children s Hospital at Westmead ( Site 3805)
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Children s Hospital ( Site 3806)
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Childrens Hospital Melbourne ( Site 3801)
• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Universitaire Ziekenhuis Antwerpen - UZA ( Site 3200)
  • Bruxelles-Capitale, Region De
    • Brussels, Bruxelles-Capitale, Region De, Belgium, 1090
      • UZ Brussel ( Site 3201)
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg ( Site 3202)
• Brazil
  • Sao Paulo, Brazil, 05403-900
    • Instituto da Crianca do Hospital das Clinicas-FMUSP ( Site 3825)
  • Parana
    • Curitiba, Parana, Brazil, 80250-060
      • Hospital Pequeno Principe ( Site 3826)
  • Rio Grande Do Sul
    • Bento Goncalves, Rio Grande Do Sul, Brazil, 95700-084
      • Hospital Tacchini ( Site 3827)
• Denmark
  • Hovedstaden
    • Copenhagen, Hovedstaden, Denmark, 2100
      • Rigshospitalet ( Site 3250)
• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00029
      • New Childrens Hospital ( Site 3750)
• France
  • Nord
    • Lille, Nord, France, 59000
      • C.H.R.U. de Lille. Hopital Jeanne de Flandres ( Site 3304)
• Guatemala
  • Guatemala, Guatemala, 01011
    • Unidad de Cirugía Cardiovascular ( Site 4126)
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont ( Site 4200)
  • Csongrad
    • Szeged, Csongrad, Hungary, 6720
      • Szegedi Tudomanyegyetem ( Site 4201)
• Malaysia
  • Kuala Lumpur, Malaysia, 50300
    • Women and Children Hospital Kuala Lumpur (Hospital Tunku Azizah) ( Site 3875)
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre. ( Site 3876)
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Sarawak General Hospital ( Site 3877)
• Mexico
  • Aguascalientes, Mexico, 20259
    • Centenario Hospital Miguel Hidalgo-Pediatrics Department ( Site 4152)
  • Colima
    • Villa De Alvarez, Colima, Mexico, 28984
      • Hospital General de Zona No. 1 ( Site 4153)
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen ( Site 4227)
  • Utrecht, Netherlands, 3584 EA
    • Wilhelmina Kinderziekenhuis ( Site 4228)
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Medical Center ( Site 4226)
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Erasmus University Medical Center ( Site 4225)
• Peru
  • Lima, Peru, 15072
    • Instituto Nacional Cardiovascular Incor ( Site 3928)
• Russian Federation
  • Kemerovskaya Oblast
    • Kemerovo, Kemerovskaya Oblast, Russian Federation, 650002
      • Scientific Research Institute Complex Problems Cardiovascular Disease ( Site 4288)
  • Moskva
    • Moscow, Moskva, Russian Federation, 117997
      • NMRC Obstetrics Gynecology and Perinatology n.a. V.I. Kulakov ( Site 4287)
    • Moscow, Moskva, Russian Federation, 117997
      • Pediatric Hematology Oncology and Immunology Centre n.a. D.Rogachev. ( Site 4275)
    • Moscow, Moskva, Russian Federation, 123001
      • Children City Clinical Hospital 13 n.a N.F.Filatov ( Site 4285)
    • Moscow, Moskva, Russian Federation, 123317
      • Children City Clinical Hospital #9 n.a. G.N.Speransky ( Site 4290)
    • Moscow, Moskva, Russian Federation, 125412
      • Scientific-Research Clinical Pediatric Institution n.a. Veltischev ( Site 4276)
  • Sankt-Peterburg
    • Saint Petersburg, Sankt-Peterburg, Russian Federation, 194100
      • St.Petersburg State Pediatric Medical University ( Site 4281)
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucille Packard Children's Hospital ( Site 3008)
  • Florida
    • Miami, Florida, United States, 33155
      • Variety Children's Hospital D.B.A. Nicklaus Children's Hospital ( Site 3019)
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Medical Center ( Site 3005)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia ( Site 3021)
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh UPMC ( Site 3017)
  • Texas
    • Houston, Texas, United States, 77030
      • McGovern Medical School at UT Health/ Memorial Hermann ( Site 3014)
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center ( Site 3013)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 2 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A. Sugammadex 2 mg/kg; Single intravenous (IV) bolus of sugammadex at 2 mg/kg	Drug: Sugammadex 2 mg/kg; 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.; Other Names: MK-8616
Experimental: Part A. Sugammadex 4 mg/kg; Single IV bolus of sugammadex at 4 mg/kg.	Drug: Sugammadex 4 mg/kg; 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).; Other Names: MK-8616
Experimental: Part B. Sugammadex 2 mg/kg; Single IV bolus of sugammadex at 2 mg/kg.	Drug: Sugammadex 2 mg/kg; 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.; Other Names: MK-8616
Experimental: Part B. Sugammadex 4 mg/kg; Single IV bolus of sugammadex at 4 mg/kg.	Drug: Sugammadex 4 mg/kg; 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).; Other Names: MK-8616
Active Comparator: Part B. Neostigmine; 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; 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.; Drug: Neostigmine + Atropine; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2019
• Primary Completion (Actual): September 21, 2023
• Study Completion (Actual): September 21, 2023

Study Registration Dates

• First Submitted: April 8, 2019
• First Submitted That Met QC Criteria: April 8, 2019
• First Posted (Actual): April 9, 2019

Study Record Updates

• Last Update Posted (Actual): October 2, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Cholinesterase Inhibitors; Mydriatics; Parasympathomimetics; Glycopyrrolate; Atropine; Neostigmine
• Other Study ID Numbers: 8616-169; MK-8616-169 (Other Identifier: Merck Protocol Number); 2017-000693-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No