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

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ClinicalTrials.gov Identifier: NCT03909165
Recruitment Status : Recruiting
First Posted : April 9, 2019
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
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 extubation.

Condition or disease Intervention/treatment Phase
Neuromuscular Blockade Drug: Sugammadex 2 mg/kg Drug: Sugammadex 4 mg/kg Drug: Neostigmine + Glycopyrrolate Drug: Neostigmine + Atropine Phase 4

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 similar to adults. For Part B participants, the efficacy of sugammadex (i.e. time to extubation / neuromuscular recovery) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Part A will be open-label, while Part B will be double-blinded.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 23, 2019
Estimated Primary Completion Date : March 23, 2023
Estimated Study Completion Date : March 23, 2023

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: 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 Name: 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.




Primary Outcome Measures :
  1. Part A. Area Under the Plasma Concentration Time Curve (AUC) for Sugammadex [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The AUC for sugammadex in plasma will be calculated.

  2. Part A. Plasma Clearance (CL) of Sugammadex [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The CL for sugammadex will be calculated.

  3. Part A. Apparent Volume of Distribution (Vz) for Sugammadex [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The Vz for sugammadex will be calculated.

  4. Part A. Apparent Volume of Distribution at Steady State (Vss) for Sugammadex [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The Vss for sugammadex will be calculated.

  5. Part A. Maximum Plasma Concentration (Cmax) of Sugammadex [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The Cmax for sugammadex will be calculated.

  6. Part A. Half-Life (t1/2) of Sugammadex in Plasma [ Time Frame: Baseline and 2, 15, 30, 60, 300, and 600 minutes post-dose ]
    The t1/2 for sugammadex will be calculated.

  7. Part B. Time to Extubation [ Time Frame: Up to 120 minutes post-dose ]
    Time to extubation will be reported, defined as the interval from administration of reversal agent to removal of the endotracheal tube.

  8. Parts A and B. Number of Participants Experiencing an Adverse Event (AE) [ Time Frame: Up to 7 days ]
    The number of participants experiencing an AE will be reported.

  9. Parts A and B. Number of Participants Discontinuing Study Due to an AE [ Time Frame: Up to 7 days ]
    The number of participants discontinuing study due to an AE will be reported.

  10. Parts A and B. Number of Participants Experiencing Treatment-emergent Relative Bradycardia [ Time Frame: Up to 30 minutes post-dose ]
    Treatment-emergent relative bradycardia is defined as a heart rate that has decreased ≥20% relative to the participant's pre-dose baseline heart rate, sustained for ≥30 seconds, and occurring after the administration of study treatment.

  11. Parts A and B. Number of Participants Experiencing Treatment-emergent Bradycardia [ Time Frame: Up to 30 minutes post-dose ]
    Treatment-emergent bradycardia is defined as a heart rate generally below the first percentile for age that has also decreased ≥20% as compared to the participant's pre-dose baseline heart rate value, sustained for ≥30 seconds, and occurring after the administration of study treatment.


Secondary Outcome Measures :
  1. Part B. Time to Neuromuscular Recovery [ Time Frame: Up to 120 minutes post-dose ]
    Time to neuromuscular recovery will be reported, defined as the interval from administration of reversal agent to neuromuscular readiness for extubation.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03909165


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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United States, California
Lucille Packard Children's Hospital ( Site 3008) Recruiting
Palo Alto, California, United States, 94304
Contact: Study Coordinator    650-724-2320      
United States, Florida
Variety Children's Hospital D.B.A. Nicklaus Children's Hospital ( Site 3019) Recruiting
Miami, Florida, United States, 33155
Contact: Study Coordinator    786-624-2853      
United States, Oklahoma
OU Medical Center ( Site 3005) Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Study Coordinator    405-698-7009      
United States, Pennsylvania
Children's Hospital of Pittsburgh UPMC ( Site 3017) Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Study Coordinator    412-692-5585      
United States, Texas
McGovern Medical School at UT Health/ Memorial Hermann ( Site 3014) Recruiting
Houston, Texas, United States, 77030
Contact: Study Coordinator    713-498-2768      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03909165     History of Changes
Other Study ID Numbers: 8616-169
2017-000693-11 ( EudraCT Number )
MK-8616-169 ( Other Identifier: Merck Protocol Number )
First Posted: April 9, 2019    Key Record Dates
Last Update Posted: September 6, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glycopyrrolate
Atropine
Neostigmine
Adjuvants, Anesthesia
Anti-Arrhythmia Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Parasympatholytics
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Cholinesterase Inhibitors
Enzyme Inhibitors
Parasympathomimetics