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

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ClinicalTrials.gov Identifier: NCT03351608
Recruitment Status : Recruiting
First Posted : November 24, 2017
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
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.

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, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 238 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
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
Actual Study Start Date : February 12, 2018
Estimated Primary Completion Date : July 22, 2020
Estimated Study Completion Date : July 22, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sugammadex 2 mg/kg (Part A)
Single intravenous (i.v.) bolus of sugammadex at 2 mg/kg.
Drug: Sugammadex 2 mg/kg
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.
Other Name: MK-8616

Experimental: Sugammadex 4 mg/kg (Part A)
Single i.v. bolus of sugammadex at 4 mg/kg.
Drug: Sugammadex 4 mg/kg
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).
Other Name: MK-8616

Experimental: Sugammadex 2 mg/kg (Part B)
Single i.v. bolus of sugammadex at 2 mg/kg.
Drug: Sugammadex 2 mg/kg
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.
Other Name: MK-8616

Experimental: Sugammadex 4 mg/kg (Part B)
Single i.v. bolus of sugammadex at 4 mg/kg.
Drug: Sugammadex 4 mg/kg
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).
Other Name: MK-8616

Active Comparator: Neostigmine (Part B)
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
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.

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 a second twitch (T2) in response to TOF stimulations.




Primary Outcome Measures :
  1. Area Under the Plasma Concentration-Time Curve (AUC) for Sugammadex [Part A] [ Time Frame: 2 minutes (min), 15 min, 30 min, 60 min, 5 hours (hrs), and 10 hrs post-dose ]
    Blood samples will be collected at prespecified time points to determine AUC, defined as the area under the curve of the plasma sugammadex concentration vs. time plot.

  2. Plasma Clearance (CL) of Sugammadex [Part A] [ Time Frame: 2 min, 15 min, 30 min, 60 min, 5 hrs, and 10 hrs post-dose ]
    Blood samples will be collected at prespecified time points to determine CL, defined as the rate of elimination relative to plasma concentration of sugammadex.

  3. Apparent Volume of Distribution (Vz) of Sugammadex [Part A] [ Time Frame: 2 min, 15 min, 30 min, 60 min, 5 hrs, and 10 hrs post-dose ]
    Blood samples will be collected at prespecified time points to determine Vz, defined as the amount of sugammadex administered relative to plasma sugammadex concentration.

  4. Maximum Plasma Concentration (Cmax) of Sugammadex [Part A] [ Time Frame: 2 min, 15 min, 30 min, 60 min, 5 hrs, and 10 hrs post-dose ]
    Blood samples will be collected at prespecified time points to determine Cmax, defined as the maximum plasma concentration of sugammadex post-administration.

  5. Plasma Half-Life of Sugammadex [Part A] [ Time Frame: 2 min, 15 min, 30 min, 60 min, 5 hrs, and 10 hrs post-dose ]
    Blood samples will be collected at prespecified time points to determine plasma half-life, defined as the time required for the plasma sugammadex concentration to decrease to 50% of maximum.

  6. Adverse Events (AEs) [Parts A and B] [ Time Frame: Up to 7 days ]
    Following administration of study intervention, the number of participants experiencing an AE will be assessed. 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. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

  7. Time to Recovery of Participant Train-Of-Four (TOF) Ratio to ≥0.9 [Part B] [ Time Frame: Up to 30 minutes post-dose ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.9 will be assessed. 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), with greater values indicating less NMB.


Secondary Outcome Measures :
  1. Time to Recovery of Participant Train-Of-Four (TOF) Ratio to ≥0.8 [Part B] [ Time Frame: Up to 30 minutes post-dose ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.8 will be assessed. 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), with greater values indicating less NMB.

  2. Time to Recovery of Participant Train-Of-Four (TOF) Ratio to ≥0.7 [Part B] [ Time Frame: Up to 30 minutes post-dose ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.7 will be assessed. 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), with greater values indicating less NMB.



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Ages Eligible for Study:   2 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT03351608


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

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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: NCT03351608     History of Changes
Other Study ID Numbers: 8616-089
2017-000692-92 ( EudraCT Number )
MK-8616-089 ( Other Identifier: Merck Protocol Number )
First Posted: November 24, 2017    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 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