Safety of Sugammadex for the Reversal of Neuromuscular Blockade in American Society of Anesthesiologists (ASA) Class 3 or 4 Participants (MK-8616-145)

A Phase 4 Randomized, Active-Comparator Controlled Clinical Trial to Study the Safety of Sugammadex (MK-8616) for the Reversal of Neuromuscular Blockade Induced by Either Rocuronium Bromide or Vecuronium Bromide in American Society of Anesthesiologists (ASA) Class 3 or 4 Subjects

The purpose of this trial is to evaluate the safety of sugammadex for the reversal of neuromuscular blockade (NMB) induced by neuromuscular blockade agents (NMBA) rocuronium or vecuronium in adult American Society of Anesthesiologists (ASA) Physical Status Class 3 and 4 participants. The primary objectives of the study are to characterize the incidence of treatment emergent sinus bradycardia, treatment emergent sinus tachycardia, or other treatment emergent cardiac arrhythmias after administration of sugammadex and to evaluate the general safety of sugammadex in a population of ASA Class 3 and 4 participants in a surgical setting.

Study Overview

• Status: Completed
• Conditions: Reversal of Neuromuscular Blockade
• Intervention / Treatment: Drug: Sugammadex 2 mg/kg; Drug: Rocuronium; Drug: Vecuronium; Drug: Sugammadex 4 mg/kg; Drug: Sugammadex 16 mg/kg; Drug: Neostigmine + Glycopyrrolate

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Feldkirch, Austria, 6800
    • Landeskrankenhaus Feldkirch ( Site 1152)
  • Wien, Austria, 1220
    • Sozialmedizinisches Zentrum Ost - Donauspital ( Site 1150)
  • Voralberg
    • Dornbirn, Voralberg, Austria, 6850
      • A.O. Krankenhaus Dornbirn ( Site 1151)
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus Universitets hospital ( Site 1252)
  • Copenhagen, Denmark, 2100
    • Rigshospitalet ( Site 1253)
  • Copenhagen NV, Denmark, 2400
    • Bispebjerg og Frederiksberg Hospital ( Site 1250)
  • Viborg, Denmark, 8800
    • Regionshospitalet Viborg ( Site 1254)
• Germany
  • Muenchen, Germany, 81675
    • Klinikum Rechts der Isar Technische Universitaet Muenchen ( Site 1350)
  • Reutlingen, Germany, 72764
    • Klinikum am Steinenberg Reutlingen ( Site 1352)
  • Warendorf, Germany, 48231
    • Josephs-Hospitals Warendorf ( Site 1351)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama - Birmingham ( Site 1046)
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University Banner Medical Center ( Site 1019)
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center ( Site 1029)
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center ( Site 1001)
  • Florida
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital ( Site 1007)
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center ( Site 1050)
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University ( Site 1057)
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation ( Site 1005)
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital ( Site 1039)
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Hospital, Royal Oak ( Site 1034)
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University Hospital- Columbia MO ( Site 1060)
    • Columbia, Missouri, United States, 65212
      • University of Missouri Health Care ( Site 1022)
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Jersey Shore University Medical Center ( Site 1058)
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital [New Brunswick, NJ] ( Site 1017)
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital - Memorial ( Site 1016)
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clin Foundation ( Site 1032)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140-5103
      • Temple University Hospital ( Site 1004)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center ( Site 1033)
  • Texas
    • Houston, Texas, United States, 77004
      • Hermann Drive Surgical Center ( Site 1021)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53295
      • Zablocki VA Medical Center ( Site 1011)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has a body mass index (BMI) < 40 kg/m2.
• Is categorized as ASA Physical Status Class 3 or 4, as determined by the Investigator.
• Has a planned surgical procedure that requires NMB with either rocuronium or vecuronium.
• Has a planned surgical procedure (e.g., gastrointestinal, urologic, or laparoscopic) that in the opinion of the investigator does not preclude maintenance of moderate or deep depth of NMB throughout the case.
• If female who is not of reproductive potential, is one of the following: (1) postmenopausal; (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; (3) has a congenital or acquired condition that prevents childbearing; or (4) is undergoing surgical sterilization (e.g., hysterectomy or tubal ligation) as the planned surgical procedure associated with participation in this study.
• If female who is sexually active and of child-bearing potential, agrees to use a medically accepted method of contraception through seven days after receiving protocol-specified medication. Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and Ethics Review Committees/Institutional Review Boards.
• Is able to provide (or the participant's legally authorized representative, in accordance with local requirements), written informed consent for the trial. The participant or legally authorized representative may also provide consent for Future Biomedical Research.

Exclusion Criteria:

• Has a pacemaker or automatic implantable cardioverter-defibrillator that precludes the assessment of bradycardia or arrhythmias.
• Has a medical condition or surgical procedure that precludes reversal of neuromuscular block at the end of surgery.
• Has a neuromuscular disorder(s) that may affect neuromuscular block and/or trial assessments.
• Is dialysis-dependent or has severe renal insufficiency, defined as estimated creatinine clearance of <30 mL/min.
• Has or is suspected of having a personal history or family history (parents, grandparents, or siblings) of malignant hyperthermia.
• Has or is suspected of having an allergy (e.g., hypersensitivity and/or anaphylactic reaction) 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 within 24 hours before or within 24 hours after study medication administration.
• Has any condition that would contraindicate the administration of study medication.
• Is pregnant, is attempting to become pregnant, or is lactating.
• Is currently participating in or has participated in an interventional clinical trial (including any other current or ongoing trial with a sugammadex treatment arm) with an investigational compound or device within 30 days of signing the informed consent form of this current trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sugammadex 2 mg/kg; Sugammadex 2 mg/kg administered as a single intravenous (IV) dose	Drug: Sugammadex 2 mg/kg; Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Sugammadex 2 mg/kg for reversal of moderate NMB. Moderate block is a level of NMB in which peripheral nerve stimulation elicits one to four muscle twitches.; Other Names: Bridion; MK-8616; Drug: Rocuronium; To achieve NMB, participants received steroidal NMBA Rocuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Vecuronium; To achieve NMB, participants received steroidal NMBA Vecuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.
EXPERIMENTAL: Sugammadex 4 mg/kg; Sugammadex 4 mg/kg administered as a single IV dose	Drug: Rocuronium; To achieve NMB, participants received steroidal NMBA Rocuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Vecuronium; To achieve NMB, participants received steroidal NMBA Vecuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Sugammadex 4 mg/kg; Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex 4 mg/kg for reversal of deep NMB. Deep block is a level of NMB in which peripheral nerve stimulation elicits no muscle twitches and high-frequency muscle stimulation elicits minimal levels of muscle contraction.; Other Names: Bridion; MK-8616
EXPERIMENTAL: Sugammadex 16 mg/kg; Sugammadex 16 mg/kg administered as a single IV dose	Drug: Rocuronium; To achieve NMB, participants received steroidal NMBA Rocuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Sugammadex 16 mg/kg; Following administration of NMBA (Rocuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex 16 mg/kg for reversal of deep NMB. Deep block is a level of NMB in which peripheral nerve stimulation elicits no muscle twitches and high-frequency muscle stimulation elicits minimal levels of muscle contraction.; Other Names: Bridion; MK-8616
ACTIVE_COMPARATOR: Neostigmine + Glycopyrrolate; Neostigmine 50 μg/kg (up to 5 mg maximum dose) plus glycopyrrolate 10 μg/kg (up to 1 mg maximum dose) administered as a single IV dose	Drug: Rocuronium; To achieve NMB, participants received steroidal NMBA Rocuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Vecuronium; To achieve NMB, participants received steroidal NMBA Vecuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.; Drug: Neostigmine + Glycopyrrolate; Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Neostigmine (50 μg/kg; 5 mg maximum) and Glycopyrrolate (10 μg/kg; 1 mg maximum) for reversal of moderate NMB. Moderate block is a level of NMB in which peripheral nerve stimulation elicits one to four muscle twitches.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events	The percentage of participants experiencing treatment-emergent sinus bradycardia events was identified with continuous electrocardiogram (ECG) monitoring. Treatment-emergent sinus bradycardia were defined as a heart rate <60 bpm that has also decreased more than 20% compared to participant baseline heart rate value, sustained for at least 1 minute after administration of study intervention. Treatment-emergent sinus bradycardia events may or may not have been considered an adverse event (AE), as determined by investigator judgment.	Up to approximately 35 minutes post-administration
Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events	The percentage of participants experiencing treatment-emergent sinus tachycardia events was identified with continuous ECG monitoring. Treatment-emergent sinus tachycardia is defined as a heart rate ≥100 bpm that has also increased more than 20% compared to participant baseline heart rate value, sustained for at least 1 minute after administration of study intervention. Treatment-emergent sinus tachycardia events may or may not have been considered an AE, as determined by investigator judgment.	Up to approximately 35 minutes post-administration
Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events	The percentage of participants experiencing other treatment-emergent cardiac arrhythmia events was identified with continuous ECG monitoring. Other treatment-emergent cardiac arrhythmias were defined as new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachycardia, ventricular fibrillation, or ventricular tachyarrhythmia), sustained for at least 1 minute after administration of study intervention. Worsening arrhythmia events may or may not have been considered an AE, as determined by investigator judgment.	Up to approximately 35 minutes post-administration
Percentage of Participants Experiencing an Adverse Event (AE) Up To 7 Days After Administration of Study Intervention	As per the protocol primary analysis, the percentage of participants experiencing an AE up to 7 days after administration of study intervention was reported. An AE was defined as any untoward medical occurrence in a participant which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE.	Up to 7 days
Percentage of Participants Experiencing a Serious Adverse Event (SAE) Up To 7 Days After Administration of Study Intervention	As per the protocol primary analysis, the percentage of participants experiencing an SAE up to 7 days after administration of study intervention was reported. An SAE was an adverse event that: resulted in death; was life threatening; resulted in persistent or significant disability or incapacity; resulted in or prolonged an existing inpatient hospitalization; was a congenital anomaly or birth defect; was an other important medical event, was a cancer; or was associated with an overdose.	Up to 7 days
Percentage of Participants Experiencing an Event of Clinical Interest (ECI) Up To 7 Days After Administration of Study Intervention	As per the protocol primary analysis, the percentage of participants experiencing an ECI up to 7 days after administration of study intervention was reported. ECIs were a discrete set of both AEs and SAEs, specifically designated as such for the trial. For the purposes of this investigation, ECIs included 1) drug-induced liver injury; 2) clinically-relevant arrhythmias, inclusive of bradycardia and tachycardia defined as events necessitating intervention, as determined by investigator judgment; and 3) instances of hypersensitivity and/or anaphylaxis adjudicated by an external expert Adjudication Committee. A participant could have experienced more than one type of ECI.	Up to 7 days

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Herring WJ, Mukai Y, Wang A, Lutkiewicz J, Lombard JF, Lin L, Watkins M, Broussard DM, Blobner M. A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants. BMC Anesthesiol. 2021 Oct 28;21(1):259. doi: 10.1186/s12871-021-01477-5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 20, 2017
• Primary Completion (ACTUAL): September 4, 2019
• Study Completion (ACTUAL): September 4, 2019

Study Registration Dates

• First Submitted: November 15, 2017
• First Submitted That Met QC Criteria: November 15, 2017
• First Posted (ACTUAL): November 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 5, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: arrhythmia, bradycardia, neuromuscular blocking agents, surgery, tachycardia
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Adjuvants, Anesthesia; Neuromuscular Agents; Cholinesterase Inhibitors; Nicotinic Antagonists; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Parasympathomimetics; Glycopyrrolate; Rocuronium; Neostigmine; Vecuronium Bromide
• Other Study ID Numbers: 8616-145; 2017-000187-15 (EUDRACT_NUMBER); MK-8616-145 (OTHER: Merck Protocol 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