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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)

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ClinicalTrials.gov Identifier: NCT03346070
Recruitment Status : Completed
First Posted : November 17, 2017
Last Update Posted : April 19, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Neuromuscular Blockade Drug: Sugammadex 2 mg/kg ABW Drug: Sugammadex 2 mg/kg IBW Drug: Sugammadex 4 mg/kg ABW Drug: Sugammadex 4 mg/kg IBW Drug: Neostigmine + Glycopyrrolate Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 207 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 4 Randomized, Active-Comparator Controlled Trial to Study the Efficacy and Safety of Sugammadex (MK-8616) for the Reversal of Neuromuscular Blockade Induced by Either Rocuronium Bromide or Vecuronium Bromide in Morbidly Obese Subjects
Actual Study Start Date : January 1, 2018
Actual Primary Completion Date : January 29, 2019
Actual Study Completion Date : January 29, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sugammadex 2 mg/kg ABW
Single intravenous (i.v.) bolus of Sugammadex at 2 mg/kg as determined utilizing participant ABW.
Drug: Sugammadex 2 mg/kg ABW

Following the final administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants will receive a single i.v. bolus of Sugammadex (2 mg/kg by ABW) for NMB reversal.

Moderate NMB is defined as the reappearance of a second twitch (T2) in response to TOF stimulations.

Other Name: MK-8616

Experimental: Sugammadex 2 mg/kg IBW
Single i.v. bolus of Sugammadex at 2 mg/kg as determined utilizing participant IBW.
Drug: Sugammadex 2 mg/kg IBW

Following the final administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants will receive a single i.v. bolus of Sugammadex (2 mg/kg by IBW) for NMB reversal.

Moderate NMB is defined as the reappearance of a second twitch (T2) in response to TOF stimulations.

Other Name: MK-8616

Experimental: Sugammadex 4 mg/kg ABW
Single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant ABW.
Drug: Sugammadex 4 mg/kg ABW

Following the final administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants will receive a single i.v. bolus of Sugammadex (4 mg/kg by ABW) for NMB reversal.

Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs).

Other Name: MK-8616

Experimental: Sugammadex 4 mg/kg IBW
Single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant IBW.
Drug: Sugammadex 4 mg/kg IBW

Following the final 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 NMB reversal.

Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs).

Other Name: MK-8616

Active Comparator: Neostigmine/Glycopyrrolate
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.
Drug: Neostigmine + Glycopyrrolate

Following the final administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants will receive 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 NMB reversal.

Moderate NMB is defined as the reappearance of a second twitch (T2) in response to TOF stimulations.





Primary Outcome Measures :
  1. Time to Recovery of Participant Train Of Four (TOF) Ratio to ≥0.9 [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.9 will be assessed through the repeated application (every 15 seconds) of the TOF electrical stimulation protocol. Specifically, 4 electrical stimulations will be applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) will be assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio (i.e. TOF ratio) indicates the current degree of NMB present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB).

  2. Percentage of Participants with Treatment-Emergent Sinus Bradycardia [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    The percentage of participants experiencing treatment-emergent bradycardia will be identified with continuous 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.

  3. Percentage of Participants with Treatment-Emergent Sinus Tachycardia [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    The percentage of participants experiencing treatment-emergent tachycardia will be 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.

  4. Percentage of Participants with Other Treatment-Emergent Cardiac Arrhythmia [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    The percentage of participants experiencing other treatment-emergent cardiac arrhythmias will be identified with continuous ECG monitoring. Other treatment-emergent cardiac arrhythmias are defined as new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachycardia, ventricular fibrillation, or ventricular tachycardia), sustained for at least 1 minute after administration of study intervention.

  5. Percentage of Participants Experiencing an Adverse Event (AE) after Administration of Study Intervention [ Time Frame: Up to 7 days ]
    The percentage of participants experiencing an AE following administration of study intervention will be 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 of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

  6. Percentage of Participants Experiencing a Serious Adverse Event (SAE) after Administration of Study Intervention [ Time Frame: Up to 7 days ]
    The percentage of participants experiencing an SAE following administration of study intervention will be 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 require medical or surgical intervention.

  7. Percentage of Participants Experiencing an Event of Clinical Interest (ECI) after Administration of Study Intervention [ Time Frame: Up to 7 days ]
    The percentage of participants experiencing an ECI following administration of study intervention will be 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 include the following: 1) drug-induced liver injury; 2) clinically-relevant arrhythmias, inclusive of bradycardia and tachycardia; and 3) instances of hypersensitivity and/or anaphylaxis.


Secondary Outcome Measures :
  1. Percentage of Participants with Prolonged (>10 minutes) Time to Recovery of the Train Of Four (TOF) ratio to ≥0.9 [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    Following administration of study intervention, the percentage of participants experiencing prolonged (>10 minutes) recovery to a TOF ratio ≥0.9 will be calculated. Recovery of the TOF ratio to ≥0.9 will be assessed through the repeated application (every 15 seconds) of the TOF electrical stimulation protocol. Specifically, 4 electrical stimulations will be applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) will be assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio (i.e. TOF ratio) indicates the current degree of NMB present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB).

  2. Time to Recovery of Participant Train Of Four (TOF) Ratio to ≥0.8 [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.8 will be assessed through the repeated application (every 15 seconds) of the TOF electrical stimulation protocol. Specifically, 4 electrical stimulations will be applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) will be assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio (i.e. TOF ratio) indicates the current degree of NMB present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB).

  3. Time to Recovery of Participant Train Of Four (TOF) Ratio to ≥0.7 [ Time Frame: Up to 30 minutes post-administration of study intervention ]
    Following administration of study intervention, the time to recovery of participant TOF ratio to ≥0.7 will be assessed through the repeated application (every 15 seconds) of the TOF electrical stimulation protocol. Specifically, 4 electrical stimulations will be applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) will be assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio (i.e. TOF ratio) indicates the current degree of NMB present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03346070


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Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03346070     History of Changes
Other Study ID Numbers: 8616-146
2017-000188-33 ( EudraCT Number )
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Body Weight
Signs and Symptoms
Glycopyrrolate
Rocuronium
Vecuronium Bromide
Neostigmine
Neuromuscular Nondepolarizing Agents
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Parasympathomimetics
Autonomic Agents
Adjuvants, Anesthesia
Muscarinic Antagonists
Cholinergic Antagonists
Nicotinic Antagonists