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 reappearance of T2 (the amplitude of the first response of second twitch to train of four (TOF) stimulation, expressed as percentage of control first twitch, T1) during sevoflurane anesthesia for Caucasian participants.
Detailed description
For most surgical procedures a depth of neuromuscular block of 1-2 twitches after TOF-stimulation is sufficient to avoid unwanted muscular activity. At reappearance of T2, the anesthesiologist might decide to either give (another) maintenance dose of rocuronium or vecuronium when surgery continues, to await spontaneous recovery of neuromuscular block or to reverse the neuromuscular block. Sugammadex has been shown in previous trials to greatly reduce the time to full recovery when administered at reappearance of T2, both after rocuronium- and vecuronium induced neuromuscular blockade. The current trial P05971 was conducted in Europe and set up to establish the dose response relationship of sugammadex given during sevoflurane anesthesia at reappearance of T2 after rocuronium or vecuronium in Caucasian participants. In addition to recovery time, also pharmacokinetics and safety of sugammadex were to be evaluated.
Interventions
DRUGSugammadex
After induction of anesthesia an intubation dose of (Neuromuscular blocking agent) NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.03 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex 0.5 to 4 mg/kg IV was administered
DRUGPlacebo
After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium (arm 1) or 0.1 mg/kg vecuronium (arm 6). Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.03 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of Placebo IV was administered
DRUGRocuronium
After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV could be administered if necessary.
DRUGVecuronium
After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV. Maintenance doses of 0.02-0.03 mg/kg vecuronium IV could be administered if necessary.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Is of American Society of Anesthesiologists (ASA) class 1 - 3; * Is at least 20 years but under 65 years of age; * Caucasian participants; * Is scheduled for elective surgery requiring muscle relaxation in supine position and under sevoflurane anesthesia with an anticipated duration of about 1.5-3 hours; * Has given written informed consent.
Exclusion criteria
* Participants in whom a difficult intubation because of anatomical malformations was expected; * Is known or suspected to have neuromuscular disorders impairing neuromuscular blocking (NMB) and/or significant renal dysfunction (for example a creatinine level \> 1.6 mg/dl) and/or severe hepatic dysfunction. * Is known or suspected to have a (family) history of malignant hyperthermia; * Is known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia; * Is receiving medication expected to interfere with the rocuronium or vecuronium given in this trial, based on the dose and time of administration; * Females who were pregnant; * Females of childbearing potential not using birth control or using only oral contraception as birth control; * Was breast-feeding; * Has already participated in P05971, or in another trial with sugammadex; * Has participated in another clinical trial, not preapproved by the Sponsor, within 6 months of entering into P05971.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.9 (up to 24 hours) | 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 Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.7 (up to 24 hours) | 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 Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.8 (up to 24 hours) | 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
Recruitment details
Caucasian participants who had a surgical procedure using a general anesthesia of rocuronium or vecuronium for endotracheal intubation and maintenance of neuromuscular block were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Rocuronium + Placebo After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of placebo was administered IV. | 10 |
| Rocuronium + 0.5 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 0.5 mg/kg sugammadex was administered IV. | 10 |
| Rocuronium + 1.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 1.0 mg/kg sugammadex was administered IV. | 9 |
| Rocuronium + 2.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 2.0 mg/kg sugammadex was administered IV. | 10 |
| Rocuronium + 4.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 4.0 mg/kg sugammadex was administered IV. | 10 |
| Vecuronium + Placebo After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.03 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of placebo was administered IV. | 10 |
| Vecuronium + 0.5 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.03 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 0.5 mg/kg sugammadex was administered IV. | 10 |
| Vecuronium + 1.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.03 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 1.0 mg/kg sugammadex was administered IV. | 10 |
| Vecuronium + 2.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.03 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 2.0 mg/kg sugammadex was administered IV. | 10 |
| Vecuronium + 4.0 mg/kg Sugammadex After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.03 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 4.0 mg/kg sugammadex was administered IV. | 9 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 2 | 0 |
| Overall Study | Not Treated | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Rocuronium + Placebo | Rocuronium + 0.5 mg/kg Sugammadex | Rocuronium + 1.0 mg/kg Sugammadex | Rocuronium + 2.0 mg/kg Sugammadex | Rocuronium + 4.0 mg/kg Sugammadex | Vecuronium + Placebo | Vecuronium + 0.5 mg/kg Sugammadex | Vecuronium + 1.0 mg/kg Sugammadex | Vecuronium + 2.0 mg/kg Sugammadex | Vecuronium + 4.0 mg/kg Sugammadex | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 50 Years STANDARD_DEVIATION 7 | 52 Years STANDARD_DEVIATION 7 | 50 Years STANDARD_DEVIATION 9 | 49 Years STANDARD_DEVIATION 8 | 49 Years STANDARD_DEVIATION 13 | 48 Years STANDARD_DEVIATION 10 | 47 Years STANDARD_DEVIATION 9 | 46 Years STANDARD_DEVIATION 9 | 45 Years STANDARD_DEVIATION 10 | 47 Years STANDARD_DEVIATION 10 | 48 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) 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) Not Hispanic or Latino | 10 Participants | 10 Participants | 9 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 9 Participants | 98 Participants |
| Ethnicity (NIH/OMB) 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 | 8 Participants | 8 Participants | 7 Participants | 5 Participants | 6 Participants | 8 Participants | 7 Participants | 7 Participants | 7 Participants | 7 Participants | 70 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 28 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 / 10 | 0 / 10 | 0 / 9 | 1 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 9 / 10 | 10 / 10 | 6 / 9 | 10 / 10 | 10 / 10 | 8 / 10 | 10 / 10 | 6 / 10 | 9 / 10 | 7 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 9 | 1 / 10 | 0 / 10 | 0 / 10 | 2 / 10 | 0 / 10 | 0 / 10 | 0 / 9 |
Outcome results
Primary
Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9
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: Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.9 (up to 24 hours)
Population: All randomized participants who received sugammadex or placebo; without any protocol violations, and who had at least one post baseline efficacy measurement, who had a TOF trace, had a reliable TOF trace, and where drug administration did not interfere with the effect of rocuronium or vecuronium.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rocuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 96.30 Minutes | Standard Deviation 33.13 |
| Rocuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 16.30 Minutes | Standard Deviation 20.6 |
| Rocuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 4.62 Minutes | Standard Deviation 5.97 |
| Rocuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 1.43 Minutes | Standard Deviation 0.5 |
| Rocuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 1.50 Minutes | Standard Deviation 0.4 |
| Vecuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 79.02 Minutes | Standard Deviation 25.97 |
| Vecuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 35.50 Minutes | Standard Deviation 42.13 |
| Vecuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 5.07 Minutes | Standard Deviation 2.38 |
| Vecuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 3.42 Minutes | Standard Deviation 1.85 |
| Vecuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9 | 3.03 Minutes | Standard Deviation 2.18 |
Secondary
Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7
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: Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.7 (up to 24 hours)
Population: All randomized participants who received sugammadex or placebo; without any protocol violations, and who had at least one post baseline efficacy measurement, who had a TOF trace, had a reliable TOF trace, and where drug administration did not interfere with the effect of rocuronium or vecuronium.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rocuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 65.67 Minutes | Standard Deviation 35.73 |
| Rocuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 3.08 Minutes | Standard Deviation 2.25 |
| Rocuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 2.08 Minutes | Standard Deviation 1.12 |
| Rocuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 1.12 Minutes | Standard Deviation 0.4 |
| Rocuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 1.02 Minutes | Standard Deviation 0.12 |
| Vecuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 58.12 Minutes | Standard Deviation 21.9 |
| Vecuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 12.57 Minutes | Standard Deviation 24.48 |
| Vecuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 2.35 Minutes | Standard Deviation 0.48 |
| Vecuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 2.00 Minutes | Standard Deviation 1.25 |
| Vecuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.7 | 1.70 Minutes | Standard Deviation 0.55 |
Secondary
Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8
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: Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.8 (up to 24 hours)
Population: All randomized participants who received sugammadex or placebo; without any protocol violations, and who had at least one post baseline efficacy measurement, who had a TOF trace, had a reliable TOF trace, and where drug administration did not interfere with the effect of rocuronium or vecuronium.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rocuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 75.85 Minutes | Standard Deviation 36.65 |
| Rocuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 6.25 Minutes | Standard Deviation 9.12 |
| Rocuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 2.62 Minutes | Standard Deviation 1.8 |
| Rocuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 1.28 Minutes | Standard Deviation 0.42 |
| Rocuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 1.15 Minutes | Standard Deviation 0.25 |
| Vecuronium + Placebo | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 64.33 Minutes | Standard Deviation 21.72 |
| Vecuronium + 0.5 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 25.65 Minutes | Standard Deviation 35.4 |
| Vecuronium + 1.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 3.10 Minutes | Standard Deviation 0.88 |
| Vecuronium + 2.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 5.83 Minutes | Standard Deviation 11.43 |
| Vecuronium + 4.0 mg/kg Sugammadex | Time From Start of Administration of Sugammadex or Placebo to Recovery of the T4/T1 Ratio to 0.8 | 2.12 Minutes | Standard Deviation 0.8 |