Neuromuscular Blockade
Conditions
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.
Interventions
DRUGSugammadex 2 mg/kg ABW
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.
DRUGSugammadex 2 mg/kg IBW
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.
DRUGSugammadex 4 mg/kg ABW
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).
DRUGSugammadex 4 mg/kg IBW
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).
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.
DRUGRocuronium or Vecuronium
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | Up to 7 days | 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). |
| Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | Up to 35 minutes | 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). |
| Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | Up to 35 minutes | 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). |
| Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | Up to 7 days | 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). |
| Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | Up to 7 days | 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). |
| Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | Up to 76 minutes | 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). |
| Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | Up to 35 minutes | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | Up to 76 minutes | The secondary efficacy analysis of TTR of participant TOF ratio to ≥0.9 was performed by estimating the geometric mean of TTR within each treatment group. 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). |
| Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | Up to 69 minutes | The efficacy analysis of TTR of participant TOF ratio to ≥0.8 was performed by estimating the geometric mean of TTR within each treatment group. 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 0.8 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). |
| Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | Up to 61 minutes | The efficacy analysis of TTR of participant TOF ratio to ≥0.7 was performed by estimating the geometric mean of TTR within each treatment group. 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 0.7 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). |
| 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 | Following administration of study intervention, the percentage of participants experiencing prolonged (\>10 minutes) recovery to a TOF ratio ≥0.9 was calculated. 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). |
Countries
Austria, Belgium, Denmark, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugammadex 2 mg/kg ABW Following administration of NMBA, participants received a single 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. | 41 |
| Sugammadex 4 mg/kg ABW 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. | 41 |
| Sugammadex 2 mg/kg IBW 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. | 41 |
| Sugammadex 4 mg/kg IBW 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. | 42 |
| Neostigmine/Glycopyrrolate 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. | 42 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Screen Failure | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Study medication not received as planned | 2 | 3 | 2 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sugammadex 2 mg/kg ABW | Sugammadex 4 mg/kg ABW | Sugammadex 2 mg/kg IBW | Sugammadex 4 mg/kg IBW | Neostigmine/Glycopyrrolate | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 47.7 Years STANDARD_DEVIATION 14.4 | 46.4 Years STANDARD_DEVIATION 11.2 | 47.6 Years STANDARD_DEVIATION 14.5 | 49.2 Years STANDARD_DEVIATION 11.7 | 47.7 Years STANDARD_DEVIATION 13.3 | 47.7 Years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 1 Participants | 5 Participants | 2 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 37 Participants | 40 Participants | 37 Participants | 39 Participants | 191 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 39 Participants | 37 Participants | 38 Participants | 38 Participants | 191 Participants |
| Sex: Female, Male Female | 34 Participants | 24 Participants | 30 Participants | 32 Participants | 29 Participants | 149 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 11 Participants | 10 Participants | 13 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 38 | 0 / 38 | 0 / 36 | 1 / 38 |
| other Total, other adverse events | 36 / 38 | 32 / 38 | 36 / 38 | 32 / 36 | 32 / 38 |
| serious Total, serious adverse events | 1 / 38 | 0 / 38 | 3 / 38 | 4 / 36 | 3 / 38 |
Outcome results
Primary
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).
Time frame: Up to 7 days
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 94.7 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 86.8 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 90.8 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 94.7 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 91.7 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 93.2 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants Experiencing an Adverse Event (AE) After Administration of Study Intervention | 89.5 Percentage of participants |
95% CI: [-12.7, 13.1]
95% CI: [-19.6, 12.2]
95% CI: [-8.1, 19.7]
95% CI: [-18, 13.1]
95% CI: [-9.6, 19.2]
95% CI: [-12.5, 17]
95% CI: [-11.4, 7.8]
Primary
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).
Time frame: Up to 7 days
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 0.0 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 2.6 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 1.3 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 2.6 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 2.8 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 2.7 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants Experiencing an Event of Clinical Interest (ECI) After Administration of Study Intervention | 2.6 Percentage of participants |
95% CI: [-13.4, 7.3]
95% CI: [-12.3, 10.8]
95% CI: [-13.7, 7]
95% CI: [-11.2, 11.7]
95% CI: [-11.5, 11]
95% CI: [-11, 12]
Primary
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).
Time frame: Up to 7 days
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 2.6 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 0.0 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 1.3 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 5.3 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 8.3 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 6.8 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants Experiencing a Serious Adverse Event (SAE) After Administration of Study Intervention | 7.9 Percentage of participants |
95% CI: [-15.2, 9.1]
95% CI: [-22.3, 1.3]
95% CI: [-18.8, 6.8]
95% CI: [-21.2, 1.8]
95% CI: [-17, 10.5]
95% CI: [-14, 15.5]
95% CI: [-13.9, 1.2]
Primary
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).
Time frame: Up to 35 minutes
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 0.0 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 0.0 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 0.0 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 2.6 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 0.0 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 1.4 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants With Other Treatment-Emergent Cardiac Arrhythmia Events | 2.6 Percentage of participants |
p-value: 0.29995% CI: [-13.9, 6.7]Miettinen & Nurminen method
p-value: >0.99995% CI: [-9.9, 9.4]Miettinen & Nurminen method
p-value: 0.32695% CI: [-13.7, 7]Miettinen & Nurminen method
p-value: 0.33595% CI: [-13.6, 7.1]Miettinen & Nurminen method
p-value: 0.93595% CI: [-11.1, 11.9]Miettinen & Nurminen method
p-value: 0.32695% CI: [-13.8, 7.3]Miettinen & Nurminen method
p-value: 0.29995% CI: [-7.5, 3.5]Miettinen & Nurminen method
Primary
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).
Time frame: Up to 35 minutes
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 5.3 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 5.3 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 5.3 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 2.6 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 5.6 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 4.1 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events | 2.6 Percentage of participants |
p-value: 0.60295% CI: [-9.6, 15]Miettinen & Nurminen method
p-value: 0.96995% CI: [-13.4, 13.5]Miettinen & Nurminen method
p-value: 0.56795% CI: [-8.7, 15]Miettinen & Nurminen method
p-value: 0.57195% CI: [-8.8, 15]Miettinen & Nurminen method
p-value: 0.9595% CI: [-11.6, 10.9]Miettinen & Nurminen method
p-value: 0.52895% CI: [-8.4, 15.9]Miettinen & Nurminen method
p-value: 0.70995% CI: [-6.8, 9.6]Miettinen & Nurminen method
Primary
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).
Time frame: Up to 35 minutes
Population: All randomized participants who received at least one dose of study treatment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 10.5 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 13.2 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 11.8 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 7.9 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 2.8 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 5.4 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants With Treatment-Emergent Sinus Tachycardia Events | 7.9 Percentage of participants |
p-value: 0.73895% CI: [-12.3, 17.4]Miettinen & Nurminen method
p-value: 0.07795% CI: [-1.7, 26.3]Miettinen & Nurminen method
p-value: 0.71795% CI: [-12, 16.4]Miettinen & Nurminen method
p-value: 0.48695% CI: [-9.9, 19.7]Miettinen & Nurminen method
p-value: 0.84995% CI: [-16.2, 12.4]Miettinen & Nurminen method
p-value: 0.33995% CI: [-18.2, 6.7]Miettinen & Nurminen method
p-value: 0.14995% CI: [-2.6, 16.8]Miettinen & Nurminen method
Primary
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).
Time frame: Up to 76 minutes
Population: All randomized participants dosed with both an NMBA and an NMB reversal agent (study treatment) with ≥1 post-randomization efficacy assessment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 1.7 Minutes |
| Sugammadex 4 mg/kg ABW | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 1.8 Minutes |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 1.8 Minutes |
| Sugammadex 2 mg/kg IBW | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 3.4 Minutes |
| Sugammadex 4 mg/kg IBW | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 3.3 Minutes |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 3.3 Minutes |
| Neostigmine/Glycopyrrolate | Time to Recovery (TTR) of Participant Train Of Four (TOF) Ratio to ≥0.9: Primary Kaplan-Meier Analysis | 34.5 Minutes |
p-value: 0.007595% CI: [1.18, 3.1]Log Rank
p-value: <0.000195% CI: [9.72, 69.03]Log Rank
p-value: <0.000195% CI: [14.13, 266.77]Log Rank
p-value: 0.000595% CI: [1.44, 3.93]Log Rank
p-value: <0.000195% CI: [1.5, 3.01]Log Rank
Secondary
Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9
Following administration of study intervention, the percentage of participants experiencing prolonged (\>10 minutes) recovery to a TOF ratio ≥0.9 was calculated. 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).
Time frame: Up to 76 minutes
Population: All randomized participants dosed with both an NMBA and an NMB reversal agent (study treatment) with ≥1 post-randomization efficacy assessment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 7.9 Percentage of participants |
| Sugammadex 4 mg/kg ABW | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 2.7 Percentage of participants |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 5.3 Percentage of participants |
| Sugammadex 2 mg/kg IBW | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 5.4 Percentage of participants |
| Sugammadex 4 mg/kg IBW | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 0.0 Percentage of participants |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 2.7 Percentage of participants |
| Neostigmine/Glycopyrrolate | Percentage of Participants With Prolonged (>10 Minutes) Time to Recovery (TTR) of the Train Of Four (TOF) Ratio to ≥0.9 | 84.2 Percentage of participants |
95% CI: [-10.8, 16.9]
95% CI: [-87.2, -57.6]
95% CI: [-88.8, -61.1]
95% CI: [-7.2, 14.2]
95% CI: [-4.8, 11]
Secondary
Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis
The efficacy analysis of TTR of participant TOF ratio to ≥0.7 was performed by estimating the geometric mean of TTR within each treatment group. 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 0.7 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).
Time frame: Up to 61 minutes
Population: All randomized participants dosed with both an NMBA and an NMB reversal agent (study treatment) with ≥1 post-randomization efficacy assessment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 1.4 Minutes |
| Sugammadex 4 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 1.3 Minutes |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 1.4 Minutes |
| Sugammadex 2 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 2.1 Minutes |
| Sugammadex 4 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 2.0 Minutes |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 2.1 Minutes |
| Neostigmine/Glycopyrrolate | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.7: Geometric Mean Analysis | 10.9 Minutes |
95% CI: [0.54, 0.81]
95% CI: [0.09, 0.17]
95% CI: [0.14, 0.27]
95% CI: [0.52, 0.83]
95% CI: [0.57, 0.77]
Secondary
Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis
The efficacy analysis of TTR of participant TOF ratio to ≥0.8 was performed by estimating the geometric mean of TTR within each treatment group. 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 0.8 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).
Time frame: Up to 69 minutes
Population: All randomized participants dosed with both an NMBA and an NMB reversal agent (study treatment) with ≥1 post-randomization efficacy assessment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 1.6 Minutes |
| Sugammadex 4 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 1.5 Minutes |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 1.5 Minutes |
| Sugammadex 2 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 2.5 Minutes |
| Sugammadex 4 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 2.6 Minutes |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 2.5 Minutes |
| Neostigmine/Glycopyrrolate | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.8: Geometric Mean Analysis | 16.6 Minutes |
95% CI: [0.5, 0.8]
95% CI: [0.07, 0.13]
95% CI: [0.11, 0.2]
95% CI: [0.44, 0.72]
95% CI: [0.51, 0.7]
Secondary
Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis
The secondary efficacy analysis of TTR of participant TOF ratio to ≥0.9 was performed by estimating the geometric mean of TTR within each treatment group. 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).
Time frame: Up to 76 minutes
Population: All randomized participants dosed with both an NMBA and an NMB reversal agent (study treatment) with ≥1 post-randomization efficacy assessment. As specified by the protocol, analysis was performed in treatment arms pooled by dosing method across depth of NMB as well as in all randomized treatment arms separated by depth of NMB.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sugammadex 2 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 2.0 Minutes |
| Sugammadex 4 mg/kg ABW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 1.9 Minutes |
| Sugammadex ABW (2 mg/kg ABW Plus 4 mg/kg ABW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 2.0 Minutes |
| Sugammadex 2 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 3.2 Minutes |
| Sugammadex 4 mg/kg IBW | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 3.5 Minutes |
| Sugammadex IBW (2 mg/kg IBW Plus 4 mg/kg IBW) | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 3.3 Minutes |
| Neostigmine/Glycopyrrolate | Time to Recovery (TTR) of Participant Train of Four (TOF) Ratio to ≥0.9: Secondary Geometric Mean Analysis | 23.1 Minutes |
95% CI: [0.48, 0.72]
95% CI: [0.48, 0.86]
95% CI: [0.06, 0.12]
95% CI: [0.1, 0.19]
95% CI: [0.4, 0.71]