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

Reversal of Neuromuscular Blockade Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03346057
• Other study ID #: 8616-145
• Secondary ID: 2017-000187-15MK
• Status: Completed
• Phase: Phase 4
• Start date: December 20, 2017
• Est. completion date: September 4, 2019

Study information

• Verified date: October 2020
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 344
• Est. completion date: September 4, 2019
• Est. primary completion date: September 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Reversal of Neuromuscular Blockade

Intervention

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.
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Countries where clinical trial is conducted

United States,  Austria,  Denmark,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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