Anesthesia, General, Neuromuscular Blockade
Conditions
Brief summary
The present trial was set up to evaluate the efficacy and safety of 2.0 mg.kg-1 sugammadex compared to neostigmine administered at reappearance of T2 in Chinese and Caucasian subjects for registration purposes in China.
Interventions
DRUGSugammadex
After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium intravenous (IV) could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 2.0 mg/kg sugammadex was administered.
DRUGneostigmine
After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 50 µg/kg neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
-Subjects who are willing to provide informed consent; be between 18 and 64 years old; are American Society of Anaesthesiology (ASA) class 1-3 (extremes included); scheduled for elective surgery under general anesthesia, allowing stable neuromuscular monitoring, which requires neuromuscular blockade using rocuronium; be compliant with the dose/visit schedules, and use an accepted method of contraception (if applicable). For China only: Subjects of Chinese descent born in China, never emigrated out of China and have a Chinese home address. For Europe only: Subjects of Caucasian descent born in Europe, never emigrated out of Europe and have a European home address.
Exclusion criteria
-Subjects with expected difficult intubation, neuromuscular disorders affecting neuromuscular blockade, significant renal/hepatic dysfunction, use of a tourniquet, (family) history of malignant hyperthermia, allergy to general anesthesia medications, contraindication to study drugs, breast feeding, pregnant, participation in previous or new trials, a clinically significant condition that may interfere with the trial, or membership in the (family of) study/sponsor staff.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. | start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade | 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. Nerve stimulation was to continue until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached \>= 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. The primary analysis was the comparison between sugammadex & neostigmine among Chinese subjects; other comparisons were secondary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade | 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. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade. |
Participant flow
Pre-assignment details
308 participants were randomized
Participants by arm
| Arm | Count |
|---|---|
| Sugammadex in Caucasian Subjects At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered. | 29 |
| Neostigmine in Caucasian Subjects At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered. | 31 |
| Sugammadex in Chinese Subjects At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered. | 120 |
| Neostigmine in Chinese Subjects At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered. | 111 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative | 0 | 1 | 3 | 5 |
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Never entered follow up | 0 | 0 | 0 | 1 |
| Overall Study | Non-compliance with protocol | 0 | 0 | 0 | 1 |
| Overall Study | Subject withdrew consent | 0 | 0 | 3 | 2 |
Baseline characteristics
| Characteristic | Neostigmine in Chinese Subjects | Total | Sugammadex in Caucasian Subjects | Neostigmine in Caucasian Subjects | Sugammadex in Chinese Subjects |
|---|---|---|---|---|---|
| Age, Continuous | 39.4 years FULL_RANGE 10.8 | 42.2 years | 52.0 years FULL_RANGE 10.3 | 51.9 years FULL_RANGE 7.3 | 39.9 years FULL_RANGE 10.8 |
| Sex: Female, Male Female | 86 Participants | 217 Participants | 25 Participants | 28 Participants | 78 Participants |
| Sex: Female, Male Male | 25 Participants | 74 Participants | 4 Participants | 3 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 29 | 26 / 31 | 73 / 120 | 84 / 111 |
| serious Total, serious adverse events | 0 / 29 | 2 / 31 | 0 / 120 | 1 / 111 |
Outcome results
Primary
Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the 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. Nerve stimulation was to continue until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached \>= 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. The primary analysis was the comparison between sugammadex & neostigmine among Chinese subjects; other comparisons were secondary.
Time frame: start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade
Population: The Full Analysis Set (FAS) population included all subjects who received randomized treatment and had at least one efficacy measurement. In the event of missing data, imputed data were used for analysis.~291 subjects received IMP, of whom two had no efficacy measurements at all. Hence the FAS consisted of 289 subjects.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sugammadex in Caucasian Subjects | Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. | 1.4 minutes |
| Neostigmine in Caucasian Subjects | Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. | 6.7 minutes |
| Sugammadex in Chinese Subjects | Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. | 1.6 minutes |
| Neostigmine in Chinese Subjects | Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. | 9.1 minutes |
Comparison: The primary analysis was the comparison of the two treatments among Chinese subjects.95% CI: [4.9, 6.6]ANOVA
Comparison: A key secondary analysis was the comparison of the two treatments among Caucasian subjects.97.5% CI: [3.7, 6]ANOVA
Comparison: A key secondary analysis was the comparison for equivalence between Chinese subjects and Caucasian subjects.97.5% CI: [-5, 21]
Secondary
Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 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. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade.
Time frame: start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade
Population: The Full Analysis Set population included all subjects who received randomized treatment and had at least one efficacy measurement. In the event of missing data, imputed data were used for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Sugammadex in Caucasian Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.7 | 1.0 minutes |
| Sugammadex in Caucasian Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.8 | 1.2 minutes |
| Neostigmine in Caucasian Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.8 | 4.6 minutes |
| Neostigmine in Caucasian Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.7 | 3.4 minutes |
| Sugammadex in Chinese Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.7 | 1.1 minutes |
| Sugammadex in Chinese Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.8 | 1.3 minutes |
| Neostigmine in Chinese Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.7 | 4.4 minutes |
| Neostigmine in Chinese Subjects | Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. | Recovery of T4/T1 ratio to 0.8 | 6.0 minutes |