Efficacy and Safety of Sugammadex Dosed According to Actual Body Weight (ABW) or Ideal Body Weight (IBW) in Reversal of Neuromuscular Blockade (NMB) in Morbidly Obese Participants (MK-8616-146)

NCT03346070 | Completed Phase 4 Results FDA Drug

• 3 other identifiers: 8616-1462017-000188-33MK-8616-146
• Study Type: interventional
• Target: 207
• Locations: 5 countries
• Sites: 24

Brief Summary

The purpose of this trial is to evaluate the safety and efficacy of Sugammadex when administered according to actual body weight (ABW) as compared to ideal body weight (IBW) for the reversal of both moderate and deep neuromuscular blockade (NMB) induced by either Rocuronium or Vecuronium in morbidly obese participants. The primary hypothesis of this investigation is that, compared to obese participants dosed based on IBW, obese participants receiving Sugammadex according to ABW will demonstrate a faster time to recovery to a Train Of Four (TOF) ratio of ≥0.9 (i.e. faster NMB reversal), pooled across NMB depth and type of neuromuscular blocking agent (NMBA; Rocuronium or Vecuronium) administered.

Conditions

Neuromuscular Blockade

Outcome Measures

Primary Outcomes (7)

• Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis

  The primary efficacy analysis of TTR of TOF ratio to ≥0.9 was performed by estimating event rates within each treatment group using the Kaplan-Meier method. TTR was monitored by applying electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to magnitudes of the first and fourth twitches respectively, after nerve stimulation. The T4/T1 ratio (TOF; expressed as a decimal of up to 1.0) indicates the extent of recovery from NMB. A faster TTR of the TOF ratio to 0.9 indicates faster recovery from NMB. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 76 minutes

• Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events

  The percentage of participants experiencing treatment-emergent bradycardia events were identified with continuous electrocardiogram (ECG) monitoring. Treatment-emergent sinus bradycardia is 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 be considered an adverse event (AE), as determined by investigator judgment. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 35 minutes

• Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events

  The percentage of participants experiencing treatment-emergent sinus tachycardia events were 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 be considered an AE, as determined by investigator judgment. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 35 minutes

• Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events

  The percentage of participants experiencing other treatment-emergent cardiac arrhythmia events were identified with continuous ECG monitoring. Other treatment-emergent cardiac arrhythmias are defined as new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachyarrhythmia, ventricular fibrillation, or ventricular tachyarrhythmia), sustained for at least 1 minute after administration of study intervention. Worsening arrhythmia events may or may not be considered an AE, as determined by investigator judgment. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 35 minutes

• Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention

  The percentage of participants experiencing an AE following administration of study intervention was monitored. An AE is 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 (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment is also considered an AE. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 7 days

• Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention

  The percentage of participants experiencing an SAE following administration of study intervention was monitored. An SAE is an adverse event that: results in death; is life threatening; results in persistent or significant disability or incapacity; results in or prolongs a hospitalization; is a congenital anomaly or birth defect; is a cancer; or may jeopardize the participant, potentially requiring medical or surgical intervention. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 7 days

• Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention

  The percentage of participants experiencing an ECI following administration of study intervention was monitored. ECIs are 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. As specified by the protocol, analyses for this outcome measure were conducted in participants pooled by dosing method across depth of NMB (Sugammadex ABW \[2 mg/kg ABW plus 4 mg/kg ABW\] and Sugammadex IBW \[2 mg/kg IBW plus 4 mg/kg IBW\]) as well as in all randomized treatment arms separated by depth of NMB (Sugammadex 2 mg/kg ABW, Sugammadex 4 mg/kg ABW, Sugammadex 2 mg/kg IBW, and Sugammadex 4 mg/kg IBW).

  Up to 7 days

Secondary Outcomes (4)

• Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9

  Up to 76 minutes

• Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis

  Up to 76 minutes

• Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis

  Up to 69 minutes

• Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis

  Up to 61 minutes

Study Arms (5)

Sugammadex 2 mg/kg ABW

EXPERIMENTAL

Following administration of NMBA, participants received a single intravenous (i.v.) bolus of Sugammadex at 2 mg/kg as determined utilizing participant ABW. A treatment dose of 2 mg/kg was used for reversal of moderate NMB.

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

Sugammadex 2 mg/kg IBW

EXPERIMENTAL

Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 2 mg/kg as determined utilizing participant IBW. A treatment dose of 2 mg/kg was used for reversal of moderate NMB.

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

Sugammadex 4 mg/kg ABW

EXPERIMENTAL

Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant ABW. A treatment dose of 4 mg/kg was used for reversal of deep NMB.

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

Sugammadex 4 mg/kg IBW

EXPERIMENTAL

Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant IBW. A treatment dose of 4 mg/kg was used for reversal of deep NMB.

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

Neostigmine/Glycopyrrolate

ACTIVE COMPARATOR

Following administration of NMBA, participants received a single i.v. bolus containing both Neostigmine (50 µg/kg; up to 5 mg maximum dose) and Glycopyrrolate (10 µg/kg; up to 1 mg maximum dose) as determined utilizing participant ABW. Neostigmine/Glycopyrrolate was used for reversal of moderate NMB. Active comparator treatment for reversal for deep NMB was not available.

Drug: Neostigmine + Glycopyrrolate; Drug: Rocuronium or Vecuronium

Interventions

Sugammadex 2 mg/kg ABW DRUG

Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Sugammadex (2 mg/kg by ABW) for reversal of moderate NMB. Moderate NMB is defined as the reappearance of a second twitch (T2) in response to TOF stimulations.

Also known as: MK-8616

Sugammadex 2 mg/kg ABW

Sugammadex 2 mg/kg IBW DRUG

Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Sugammadex (2 mg/kg by IBW) for reversal of moderate NMB. Moderate NMB is defined as the reappearance of T2 in response to TOF stimulations.

Also known as: MK-8616

Sugammadex 2 mg/kg IBW

Sugammadex 4 mg/kg ABW DRUG

Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex (4 mg/kg by ABW) for reversal of deep NMB. Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs).

Also known as: MK-8616

Sugammadex 4 mg/kg ABW

Sugammadex 4 mg/kg IBW DRUG

Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants will receive a single i.v. bolus of Sugammadex (4 mg/kg by IBW) for reversal of deep NMB. Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs).

Also known as: MK-8616

Sugammadex 4 mg/kg IBW

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), dosed according to participant ABW for reversal of moderate NMB. Moderate NMB is defined as the reappearance of T2 in response to TOF stimulations.

Neostigmine/Glycopyrrolate

Rocuronium or Vecuronium DRUG

To achieve NMB, participants received steroidal NMBA Rocuronium Bromide or Vecuronium Bromide administered via i.v. infusion and dosed according to participant ABW. NMBAs were concomitant medications used per label as adjunct to general anesthesia.

Neostigmine/Glycopyrrolate; Sugammadex 2 mg/kg ABW; Sugammadex 2 mg/kg IBW; Sugammadex 4 mg/kg ABW; Sugammadex 4 mg/kg IBW

Eligibility Criteria

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

You may qualify if:

• Have BMI ≥40 kg/m² (morbidly obese).
• Be categorized as American Society of Anesthesiologists (ASA) Physical Status Class 3
• Have a planned surgical procedure that requires neuromuscular block with either rocuronium or vecuronium.
• Have a planned surgical procedure (e.g., gastrointestinal, urologic, or laparoscopic procedures) that in the opinion of the investigator does not preclude maintenance of moderate or deep depth of NMB throughout the case (maintained by re-dosing or continuous infusion).
• Have a planned surgical procedure that would allow objective neuromuscular monitoring techniques to be applied with access to the arm for neuromuscular transmission monitoring.
• If female, who is not of reproductive potential, be one of the following: 1) postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age; 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 as the planned surgical procedure associated with participation in this study (e.g., hysterectomy or tubal ligation).
• 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. Please note the following: 1) Medically accepted methods of contraception include condoms (male or female) with a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), inert or copper-containing IUD, surgical sterilization (e.g., hysterectomy or tubal ligation); 2) 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 Human Subjects Protection Review Boards; 3 Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception; 4) If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.
• Be able to provide (or the subject'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:

• Have an actual body weight \<100 kg.
• Have a pacemaker or automatic implantable cardioverter-defibrillator that precludes the assessment of bradycardia or arrhythmias.
• Have a medical condition or surgical procedure that precludes reversal of neuromuscular block at the end of surgery.
• Have neuromuscular disorder(s) that may affect neuromuscular block and/or trial assessments.
• Are dialysis-dependent or have severe renal insufficiency (defined as estimated creatinine clearance of \<30 mL/min.).
• Have or are suspected of having a personal history or family history (parents, grandparents, or siblings) of malignant hyperthermia.
• Have or are 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.
• Have received or are planning to receive toremifene within 24 hours before or within 24 hours after study medication administration.
• Have any condition that would contraindicate the administration of study medication.
• Are currently pregnant, attempting to become pregnant, or lactating.
• Have any clinically significant condition or situation (e.g., 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.
• Are currently participating in or has participated in an interventional clinical trial with an investigational compound (including any other current or ongoing trial with a Sugammadex treatment arm) or device within 30 days of signing the informed consent form of this current trial.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (24)

University California / Davis ( Site 2001)

Sacramento, California, 95817, United States

Location

Jackson Memorial Hospital/University of Miami ( Site 2007)

Miami, Florida, 33136, United States

Location

University of Kansas Medical Center ( Site 2049)

Kansas City, Kansas, 66160, United States

Location

William Beaumont Hospital - Royal Oak ( Site 2033)

Royal Oak, Michigan, 48073, United States

Location

University Hospital- Columbia MO ( Site 2060)

Columbia, Missouri, 65212, United States

Location

Robert Wood Johnson University Hospital ( Site 2037)

New Brunswick, New Jersey, 08901, United States

Location

Mission Hospital - St. Joseph ( Site 2015)

Asheville, North Carolina, 28801, United States

Location

Cleveland Clinic Foundation ( Site 2031)

Cleveland, Ohio, 44195, United States

Location

Temple University Hospital ( Site 2004)

Philadelphia, Pennsylvania, 19140, United States

Location

Vanderbilt University Medical Center ( Site 2032)

Nashville, Tennessee, 37232, United States

Location

Hermann Drive Surgical Center ( Site 2020)

Houston, Texas, 77004, United States

Location

Hermann Drive Surgical Center ( Site 2059)

Houston, Texas, 77004, United States

Location

Zablocki VA Medical Center ( Site 2011)

Milwaukee, Wisconsin, 53295, United States

Location

Sozialmedizinisches Zentrum Ost - Donauspital ( Site 2150)

Vienna, 1220, Austria

Location

Universitaire Ziekenhuis Antwerpen - UZA ( Site 2200)

Edegem, 2650, Belgium

Location

Rigshospitalet ( Site 2253)

Copenhagen, 2100, Denmark

Location

Bispebjerg og Frederiksberg Hospital ( Site 2250)

Copenhagen NV, 2400, Denmark

Location

Johanniter Krankenhaus Bonn ( Site 2353)

Bonn, 53113, Germany

Location

Diakovere Annastift gGmbH ( Site 2355)

Hanover, 30625, Germany

Location

Universitatsklinikum Giessen und Marburg GmbH ( Site 2356)

Marburg, 35043, Germany

Location

Klinikum Rechts der Isar Technische Universitaet Muenchen ( Site 2350)

München, 81675, Germany

Location

St. Franziskus-Hospital ( Site 2354)

Münster, 48145, Germany

Location

Klinikum am Steinenberg Reutlingen ( Site 2352)

Reutlingen, 72764, Germany

Location

Josephs-Hospitals Warendorf ( Site 2351)

Warendorf, 48231, Germany

Location

Related Publications (2)

• Mostoller K, Wrishko R, Maganti L, Herring WJ, van Zutphen-van Geffen M. Pharmacokinetics of Sugammadex Dosed by Actual and Ideal Body Weight in Patients With Morbid Obesity Undergoing Surgery. Clin Transl Sci. 2021 Mar;14(2):737-744. doi: 10.1111/cts.12941. Epub 2020 Dec 16.

  PMID: 33278332 BACKGROUND

• Horrow JC, Li W, Blobner M, Lombard J, Speek M, DeAngelis M, Herring WJ. Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromuscular block: a randomized clinical trial. BMC Anesthesiol. 2021 Feb 27;21(1):62. doi: 10.1186/s12871-021-01278-w.

  PMID: 33639839 DERIVED

MeSH Terms

Interventions

Sugammadex; Neostigmine; Glycopyrrolate; Rocuronium; Vecuronium Bromide

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: January 1, 2018
• Primary Completion: January 29, 2019
• Study Completion: January 29, 2019
• Last Updated: January 28, 2021
• Results First Posted: December 23, 2019

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); US (13); DE (7); BE (1); DK (2)