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

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ClinicalTrials.gov Identifier: NCT03346057
Recruitment Status : Completed
First Posted : November 17, 2017
Results First Posted : October 8, 2020
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE November 15, 2017
First Posted Date  ICMJE November 17, 2017
Results First Submitted Date  ICMJE August 24, 2020
Results First Posted Date  ICMJE October 8, 2020
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE December 20, 2017
Actual Primary Completion Date September 4, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
  • Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events [ Time Frame: Up to approximately 35 minutes post-administration ]
    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.
  • Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events [ Time Frame: Up to approximately 35 minutes post-administration ]
    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.
  • Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events [ Time Frame: Up to approximately 35 minutes post-administration ]
    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.
  • Percentage of Participants Experiencing an Adverse Event (AE) Up To 7 Days After Administration of Study Intervention [ Time Frame: Up to 7 days ]
    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.
  • Percentage of Participants Experiencing a Serious Adverse Event (SAE) Up To 7 Days After Administration of Study Intervention [ Time Frame: Up to 7 days ]
    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.
  • Percentage of Participants Experiencing an Event of Clinical Interest (ECI) Up To 7 Days After Administration of Study Intervention [ Time Frame: Up to 7 days ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 15, 2017)
  • Percentage of Participants Experiencing Treatment Emergent Sinus Bradycardia After Administration of Sugammadex [ Time Frame: 30 minutes post-administration ]
    Sinus bradycardia is defined as a heart rate <60 bpm which has also decreased more than 20% compared to the participant's baseline heart rate value, and has been sustained for at least 1 minute after administration of study treatment.
  • Percentage of Participants Experiencing Treatment Emergent Sinus Tachycardia After Administration of Sugammadex [ Time Frame: 30 minutes post-administration ]
    Sinus tachycardia is defined as a heart rate >=100 bpm which has also decreased more than 20% compared to the participant's baseline heart rate value, and has been sustained for at least 1 minute after administration of study treatment.
  • Percentage of Participants Experiencing Treatment Emergent Cardiac Arrhythmias After Administration of Sugammadex [ Time Frame: 30 minutes post-administration ]
    The percentage of participants experiencing treatment emergent cardiac arrhythmias necessitating intervention (e. g., new or worsening atrial fibrillation, atrial tachycardia, ventricular tachycardia, or ventricular fibrillation) The arrhythmia has been sustained for at least 1 minute after administration of study treatment.
  • Percentage of Participants Experiencing One or More Adverse Events After Treatment with Sugammadex [ Time Frame: Up to 7 days ]
  • Percentage of Participants Experiencing Hypersensitivity or Anaphylaxis [ Time Frame: Up to 7 days ]
  • Percentage of Participants Experiencing Sinus Bradycardia or Sinus Tachycardia Necessitating Intervention [ Time Frame: Up to 7 days ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety of Sugammadex for the Reversal of Neuromuscular Blockade in American Society of Anesthesiologists (ASA) Class 3 or 4 Participants (MK-8616-145)
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Reversal of Neuromuscular Blockade
Intervention  ICMJE
  • 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:
    • MK-8616
    • Bridion
  • 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:
    • MK-8616
    • Bridion
  • 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:
    • MK-8616
    • Bridion
  • 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.
  • 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.
Study Arms  ICMJE
  • Experimental: Sugammadex 2 mg/kg
    Sugammadex 2 mg/kg administered as a single intravenous (IV) dose
    Interventions:
    • Drug: Sugammadex 2 mg/kg
    • Drug: Rocuronium
    • Drug: Vecuronium
  • Experimental: Sugammadex 4 mg/kg
    Sugammadex 4 mg/kg administered as a single IV dose
    Interventions:
    • Drug: Sugammadex 4 mg/kg
    • Drug: Rocuronium
    • Drug: Vecuronium
  • Experimental: Sugammadex 16 mg/kg
    Sugammadex 16 mg/kg administered as a single IV dose
    Interventions:
    • Drug: Sugammadex 16 mg/kg
    • Drug: Rocuronium
  • 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
    Interventions:
    • Drug: Neostigmine + Glycopyrrolate
    • Drug: Rocuronium
    • Drug: Vecuronium
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 21, 2020)
344
Original Estimated Enrollment  ICMJE
 (submitted: November 15, 2017)
331
Actual Study Completion Date  ICMJE September 4, 2019
Actual Primary Completion Date September 4, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Denmark,   Germany,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03346057
Other Study ID Numbers  ICMJE 8616-145
2017-000187-15 ( EudraCT Number )
MK-8616-145 ( Other Identifier: Merck Protocol Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Current Responsible Party Merck Sharp & Dohme LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP