Anesthesia, General
Conditions
Brief summary
The objective of the trial was to establish the dose-response relation of sugammadex (Org 25969) given as a reversal agent of rocuronium or vecuronium at 1-2 PTC during sevoflurane anesthesia for Japanese participants.
Interventions
DRUGSugammadex
After induction of anesthesia an intubation dose of a neuromuscular blocking agent (NMBA) was administered IV: either 0.9 mg/kg rocuronium (arms 1-5) or 0.1 mg/kg vecuronium (arms 6-10). Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 8.0 mg/kg) IV was administered.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants of American Society of Anesthesiologists (ASA) class 1 - 3; * Participants at least 20 years but under 65 years of age; * Japanese participants; * Participants scheduled for elective surgery in supine position and under sevoflurane anesthesia, in need of administration of a neuromuscular blocking agent (NMBA), with an anticipated duration of about 1.5-3 hours; * Participants who had given written informed consent. This was obtained before the investigator or the sub-investigator performed any procedures or assessments for the screening, and after the participant was informed about the nature and purpose of the study, the study procedures, and the risks and restrictions of the study.
Exclusion criteria
* Participants in whom a difficult intubation because of anatomical malformations was expected; * Participants known or suspected to have neuromuscular disorders impairing neuromuscular blockade (NMB) and/or significant renal dysfunction (for example a creatinine level \> 1.6 mg/dl) and/or severe hepatic dysfunction. * Participants known or suspected to have a (family) history of malignant hyperthermia; * Participants known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia; * Participants receiving medication expected to interfere with the rocuronium or vecuronium given in this trial, based on the dose and time of administration; * Female participants who were pregnant; * Female participants of childbearing potential not using birth control or using only oral contraception as birth control; * Participants who were breast-feeding; * Participants who had already participated in study CT 19.4.209A, or in another trial with sugammadex; * Participants who had participated in another clinical trial within 6 months of entering into study CT 19.4.209A.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | Up to 269:45 (min:sec) | Neuromuscular functioning was monitored by applying repetitive Train-Of-Four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from neuromuscular blockade (NMB). In this study, twitch responses were recorded until the T4/T1 Ratio reached \>= 0.9, the minimum acceptable ratio that indicated recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.9 indicates a faster recovery from NMB. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | Up to 152:30 (min:sec) | Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.7 indicates a faster recovery from NMB. |
| Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | Up to 194:45 (min:sec) | Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.8 indicates a faster recovery from NMB. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugammadex 0.5 mg/kg (Rocuronium) Sugammadex 0.5 mg/kg administered as a single-bolus intravenous (IV) dose at 1-2 Post-tetanic count (PTC) after 0.9 mg/kg rocuronium (single-bolus IV dose) for intubation, followed by maintenance doses of rocuronium 0.1-0.2 mg/kg if necessary | 9 |
| Sugammadex 1.0 mg/kg (Rocuronium) Sugammadex 1.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.9 mg/kg rocuronium (single-bolus IV dose) for intubation, followed by maintenance doses of rocuronium 0.1-0.2 mg/kg if necessary | 9 |
| Sugammadex 2.0 mg/kg (Rcocuronium) Sugammadex 2.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.9 mg/kg rocuronium (single-bolus IV dose) for intubation, followed by maintenance doses of rocuronium 0.1-0.2 mg/kg if necessary | 10 |
| Sugammadex 4.0 mg/kg (Rocuronium) Sugammadex 4.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.9 mg/kg rocuronium (single-bolus IV dose) for intubation, followed by maintenance doses of rocuronium 0.1-0.2 mg/kg if necessary | 11 |
| Sugammadex 8.0 mg/kg (Rocuronium) Sugammadex 8.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.9 mg/kg rocuronium (single-bolus IV dose) for intubation, followed by maintenance doses of rocuronium 0.1-0.2 mg/kg if necessary | 10 |
| Sugammadex 0.5 mg/kg (Vecuronium) Sugammadex 0.5 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.1 mg/kg vecuronium (single-bolus IV dose) for intubation, followed by maintenance doses of vecuronium 0.02-0.04 mg/kg if necessary | 10 |
| Sugammadex 1.0 mg/kg (Vecuronium) Sugammadex 1.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.1 mg/kg vecuronium (single-bolus IV dose) for intubation, followed by maintenance doses of vecuronium 0.02-0.04 mg/kg if necessary | 10 |
| Sugammadex 2.0 mg/kg (Vecuronium) Sugammadex 2.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.1 mg/kg vecuronium (single-bolus IV dose) for intubation, followed by maintenance doses of vecuronium 0.02-0.04 mg/kg if necessary | 10 |
| Sugammadex 4.0 mg/kg (Vecuronium) Sugammadex 4.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.1 mg/kg vecuronium (single-bolus IV dose) for intubation, followed by maintenance doses of vecuronium 0.02-0.04 mg/kg if necessary | 10 |
| Sugammadex 8.0 mg/kg (Vecuronium) Sugammadex 8.0 mg/kg administered as a single-bolus IV dose at 1-2 PTC after 0.1 mg/kg vecuronium (single-bolus IV dose) for intubation, followed by maintenance doses of vecuronium 0.02-0.04 mg/kg if necessary | 10 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal of Informed Consent | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sugammadex 0.5 mg/kg (Rocuronium) | Sugammadex 1.0 mg/kg (Rocuronium) | Sugammadex 2.0 mg/kg (Rcocuronium) | Sugammadex 4.0 mg/kg (Rocuronium) | Sugammadex 8.0 mg/kg (Rocuronium) | Sugammadex 0.5 mg/kg (Vecuronium) | Sugammadex 1.0 mg/kg (Vecuronium) | Sugammadex 2.0 mg/kg (Vecuronium) | Sugammadex 4.0 mg/kg (Vecuronium) | Sugammadex 8.0 mg/kg (Vecuronium) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 13 | 48 years STANDARD_DEVIATION 13 | 45 years STANDARD_DEVIATION 13 | 48 years STANDARD_DEVIATION 13 | 44 years STANDARD_DEVIATION 13 | 44 years STANDARD_DEVIATION 14 | 51 years STANDARD_DEVIATION 10 | 40 years STANDARD_DEVIATION 13 | 38 years STANDARD_DEVIATION 11 | 50 years STANDARD_DEVIATION 12 | 45 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Japanese Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Japanese Not Hispanic or Latino | 9 Participants | 9 Participants | 10 Participants | 11 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Japanese Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 8 Participants | 4 Participants | 3 Participants | 5 Participants | 4 Participants | 5 Participants | 45 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 7 Participants | 8 Participants | 2 Participants | 6 Participants | 7 Participants | 5 Participants | 6 Participants | 5 Participants | 54 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 9 / 9 | 9 / 9 | 10 / 10 | 11 / 11 | 10 / 10 | 10 / 10 | 9 / 10 | 10 / 10 | 9 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 9 | 1 / 9 | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 | 1 / 10 | 1 / 10 | 0 / 10 |
Outcome results
Primary
Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation
Neuromuscular functioning was monitored by applying repetitive Train-Of-Four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from neuromuscular blockade (NMB). In this study, twitch responses were recorded until the T4/T1 Ratio reached \>= 0.9, the minimum acceptable ratio that indicated recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.9 indicates a faster recovery from NMB.
Time frame: Up to 269:45 (min:sec)
Population: The analysis population consisted of all randomized participants who were given at least one administration of sugammadex and had at least one post-baseline efficacy measurement, without any major protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex 0.5 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 66.90 Minutes | Standard Deviation 34.63 |
| Sugammadex 1.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 4.73 Minutes | Standard Deviation 1.73 |
| Sugammadex 2.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 3.43 Minutes | Standard Deviation 2.52 |
| Sugammadex 4.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 1.58 Minutes | Standard Deviation 0.88 |
| Sugammadex 8.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 1.32 Minutes | Standard Deviation 0.57 |
| Sugammadex 0.5 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 79.48 Minutes | Standard Deviation 46.23 |
| Sugammadex 1.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 39.82 Minutes | Standard Deviation 45.77 |
| Sugammadex 2.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 16.02 Minutes | Standard Deviation 42.2 |
| Sugammadex 4.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 3.05 Minutes | Standard Deviation 2.38 |
| Sugammadex 8.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.9 for Train-Of-Four (TOF) Stimulation | 2.93 Minutes | Standard Deviation 3.77 |
Secondary
Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation
Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.7 indicates a faster recovery from NMB.
Time frame: Up to 152:30 (min:sec)
Population: The analysis population was the Per-Protocol (PP) group, which consisted of all randomized participants who were given at least one administration of sugammadex and had at least one post-baseline efficacy measurement, without any major protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex 0.5 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 34.45 Minutes | Standard Deviation 32.12 |
| Sugammadex 1.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 4.38 Minutes | Standard Deviation 2.32 |
| Sugammadex 2.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 2.48 Minutes | Standard Deviation 2 |
| Sugammadex 4.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 1.07 Minutes | Standard Deviation 0.2 |
| Sugammadex 8.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 1.03 Minutes | Standard Deviation 0.32 |
| Sugammadex 0.5 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 56.82 Minutes | Standard Deviation 35.47 |
| Sugammadex 1.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 8.30 Minutes | Standard Deviation 10.9 |
| Sugammadex 2.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 3.18 Minutes | Standard Deviation 3.72 |
| Sugammadex 4.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 1.95 Minutes | Standard Deviation 1.35 |
| Sugammadex 8.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.7 for TOF Stimulation | 1.33 Minutes | Standard Deviation 0.58 |
Secondary
Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation
Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.8 indicates a faster recovery from NMB.
Time frame: Up to 194:45 (min:sec)
Population: The analysis population consisted of all randomized participants who were given at least one administration of sugammadex and had at least one post-baseline efficacy measurement, without any major protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex 0.5 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 46.78 Minutes | Standard Deviation 30.85 |
| Sugammadex 1.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 4.33 Minutes | Standard Deviation 1.85 |
| Sugammadex 2.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 2.98 Minutes | Standard Deviation 2.17 |
| Sugammadex 4.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 1.33 Minutes | Standard Deviation 0.58 |
| Sugammadex 8.0 mg/kg (Rocuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 1.13 Minutes | Standard Deviation 0.4 |
| Sugammadex 0.5 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 73.25 Minutes | Standard Deviation 45.65 |
| Sugammadex 1.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 22.60 Minutes | Standard Deviation 27.9 |
| Sugammadex 2.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 6.02 Minutes | Standard Deviation 11.83 |
| Sugammadex 4.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 2.22 Minutes | Standard Deviation 1.48 |
| Sugammadex 8.0 mg/kg (Vecuronium) | Time From Start of Sugammadex Administration to Recovery of the Neuromuscular Response to a Ratio of 0.8 for TOF Stimulation | 1.42 Minutes | Standard Deviation 0.53 |