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

NCT03346057 | Completed Phase 4 Results FDA Drug

• 3 other identifiers: 8616-1452017-000187-15MK-8616-145
• Study Type: interventional
• Target: 344
• Locations: 4 countries
• Sites: 30

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.

Conditions

Reversal of Neuromuscular Blockade

Keywords

arrhythmia, bradycardia, neuromuscular blocking agents, surgery, tachycardia

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (4)

Sugammadex 2 mg/kg

EXPERIMENTAL

Sugammadex 2 mg/kg administered as a single intravenous (IV) dose

Drug: Sugammadex 2 mg/kg; Drug: Rocuronium; Drug: Vecuronium

Sugammadex 4 mg/kg

EXPERIMENTAL

Sugammadex 4 mg/kg administered as a single IV dose

Drug: Sugammadex 4 mg/kg; Drug: Rocuronium; Drug: Vecuronium

Sugammadex 16 mg/kg

EXPERIMENTAL

Sugammadex 16 mg/kg administered as a single IV dose

Drug: Sugammadex 16 mg/kg; Drug: Rocuronium

Neostigmine + Glycopyrrolate

ACTIVE COMPARATOR

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: Neostigmine + Glycopyrrolate; Drug: Rocuronium; Drug: Vecuronium

Interventions

Sugammadex 2 mg/kg DRUG

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.

Also known as: MK-8616, Bridion

Sugammadex 2 mg/kg

Sugammadex 4 mg/kg DRUG

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.

Also known as: MK-8616, Bridion

Sugammadex 4 mg/kg

Sugammadex 16 mg/kg DRUG

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.

Also known as: MK-8616, Bridion

Sugammadex 16 mg/kg

Neostigmine + Glycopyrrolate DRUG

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.

Neostigmine + Glycopyrrolate

Rocuronium DRUG

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.

Neostigmine + Glycopyrrolate; Sugammadex 16 mg/kg; Sugammadex 2 mg/kg; Sugammadex 4 mg/kg

Vecuronium DRUG

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.

Neostigmine + Glycopyrrolate; Sugammadex 2 mg/kg; Sugammadex 4 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (30)

University of Alabama - Birmingham ( Site 1046)

Birmingham, Alabama, 35233, United States

Location

University Banner Medical Center ( Site 1019)

Tucson, Arizona, 85719, United States

Location

Loma Linda University Medical Center ( Site 1029)

Loma Linda, California, 92354, United States

Location

University of California Davis Medical Center ( Site 1001)

Sacramento, California, 95817, United States

Location

Jackson Memorial Hospital ( Site 1007)

Miami, Florida, 33136, United States

Location

University of Kansas Medical Center ( Site 1050)

Kansas City, Kansas, 66160, United States

Location

Tulane University ( Site 1057)

New Orleans, Louisiana, 70112, United States

Location

Ochsner Clinic Foundation ( Site 1005)

New Orleans, Louisiana, 70121, United States

Location

Brigham & Women's Hospital ( Site 1039)

Boston, Massachusetts, 02115, United States

Location

Beaumont Hospital, Royal Oak ( Site 1034)

Royal Oak, Michigan, 48073, United States

Location

University Hospital- Columbia MO ( Site 1060)

Columbia, Missouri, 65212, United States

Location

University of Missouri Health Care ( Site 1022)

Columbia, Missouri, 65212, United States

Location

Jersey Shore University Medical Center ( Site 1058)

Neptune City, New Jersey, 07753, United States

Location

Saint Peter's University Hospital [New Brunswick, NJ] ( Site 1017)

New Brunswick, New Jersey, 08901, United States

Location

Mission Hospital - Memorial ( Site 1016)

Asheville, North Carolina, 28801, United States

Location

Cleveland Clin Foundation ( Site 1032)

Cleveland, Ohio, 44195, United States

Location

Temple University Hospital ( Site 1004)

Philadelphia, Pennsylvania, 19140-5103, United States

Location

Vanderbilt University Medical Center ( Site 1033)

Nashville, Tennessee, 37232, United States

Location

Hermann Drive Surgical Center ( Site 1021)

Houston, Texas, 77004, United States

Location

Zablocki VA Medical Center ( Site 1011)

Milwaukee, Wisconsin, 53295, United States

Location

A.O. Krankenhaus Dornbirn ( Site 1151)

Dornbirn, Voralberg, 6850, Austria

Location

Landeskrankenhaus Feldkirch ( Site 1152)

Feldkirch, 6800, Austria

Location

Sozialmedizinisches Zentrum Ost - Donauspital ( Site 1150)

Vienna, 1220, Austria

Location

Aarhus Universitets hospital ( Site 1252)

Aarhus, 8200, Denmark

Location

Rigshospitalet ( Site 1253)

Copenhagen, 2100, Denmark

Location

Bispebjerg og Frederiksberg Hospital ( Site 1250)

Copenhagen NV, 2400, Denmark

Location

Regionshospitalet Viborg ( Site 1254)

Viborg, 8800, Denmark

Location

Klinikum Rechts der Isar Technische Universitaet Muenchen ( Site 1350)

München, 81675, Germany

Location

Klinikum am Steinenberg Reutlingen ( Site 1352)

Reutlingen, 72764, Germany

Location

Josephs-Hospitals Warendorf ( Site 1351)

Warendorf, 48231, Germany

Location

Related Publications (1)

• 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.

  PMID: 34711192 DERIVED

MeSH Terms

Conditions

Arrhythmias, Cardiac; Bradycardia; Tachycardia

Interventions

Sugammadex; Neostigmine; Glycopyrrolate; Rocuronium; Vecuronium Bromide

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cardiac Conduction System Disease

Intervention Hierarchy (Ancestors)

gamma-Cyclodextrins; Cyclodextrins; Macrocyclic Compounds; Polycyclic Compounds; Dextrins; Starch; Glucans; Polysaccharides; Carbohydrates; Phenylammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Onium Compounds; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Androstanols; Androstanes; Steroids; Fused-Ring Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2017
• First Posted: November 17, 2017
• Study Start: December 20, 2017
• Primary Completion: September 4, 2019
• Study Completion: September 4, 2019
• Last Updated: October 8, 2020
• Results First Posted: October 8, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share

Locations

DK (4); US (20); AU (3); DE (3)