Anesthesia
Conditions
Brief summary
The current trial was designed to investigate the effects of 4.0 mg.kg-1 of sugammadex on efficacy, safety and pharmacokinetics in subjects with severe renal impairment in comparison to subjects with normal renal function.
Detailed description
The results of previous trials showed that the safety profile of sugammadex observed in subjects with impaired renal function are not appreciably different from subjects with normal renal function. Reoccurrence of neuromuscular blockade was not observed, and sugammadex was safe and generally well tolerated in subjects with severe renal impairment. In a previous trial, subjects (n=15) with severe renal impairment received a dose of 2.0 mg.kg-1 of sugammadex. The effects of the other proposed recommended dose for routine reversal, 4.0 mg.kg-1, on efficacy, safety and pharmacokinetics had not been studied thus far in subjects with severe renal impairment. The objectives of this trial were to assess equivalence with respect to the efficacy of sugammadex in subjects with normal renal function or severe renal impairment, to evaluate the safety of sugammadex in these subject groups and to compare the pharmacokinetic profiles.
Interventions
DRUGsugammadex
Each subject will receive an intravenous (i.v.) single bolus dose of 0.6 mg.kg-1 rocuronium. After this dose, maintenance doses of 0.1 - 0.2 mg.kg-1 rocuronium may be given. In case of maintenance dosing, the target depth of neuromuscular blockade has to be maintained at 1-2 post-tetanic counts (PTC). After the last dose of rocuronium has been administered, the subject will receive a single bolus dose of 4.0 mg.kg-1 sugammadex at a target depth of blockade of 1-2 PTC.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age * ASA class 1-3 * Creatinine clearance (CLcr) \< 30 mL/min and no anticipated clinical indication for high flux hemodialysis during first 24 hours after sugammadex administration (for renally impaired group) or CLcr \>= 80 mL/min (for control group) -Scheduled for a surgical procedure under general anesthesia with propofol requiring neuromuscular relaxation with the use of rocuronium * Scheduled for a surgical procedure in supine position * Written informed consent
Exclusion criteria
\- Subjects known or suspected to have neuromuscular disorders impairing neuromuscular blockade and/or significant hepatic dysfunction * Subjects scheduled for renal transplant surgery * Subjects known or suspected to have a (family) history of malignant hyperthermia -Subjects known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia * Subjects receiving fusidic acid, toremifene and/or flucloxacillin * Subjects who have already participated in a sugammadex trial * Subjects who have participated in another clinical trial, not pre-approved by the sponsor, within 30 days of entering into 19.4.328 (P05769) * Female subjects who are pregnant * Female subjects who are breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recovery of the T4/T1 Ratio to 0.9. | start of administration of sugammadex 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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recovery of the T4/T1 Ratio to 0.8 | start of administration of sugammadex 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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. |
| Time to Recovery of T4/T1 Ratio to 0.7 | start of administration of sugammadex 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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participants With Severe Renal Impairment Participants with severe renal impairment will receive a single bolus dose of 4.0 mg.kg-1 sugammadex at a target depth of blockade of 1-2 PTC. Severe renal impairment was defined as creatinine clearance \<30mL/min. | 35 |
| Participants With Normal Renal Function Participants with normal renal impairment will receive a single bolus dose of 4.0 mg.kg-1 sugammadex at a target depth of blockade of 1-2 PTC. Normal renal function was defined as creatinine clearance \>=80mL/min. | 33 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Participants With Severe Renal Impairment | Participants With Normal Renal Function | Total |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 16 | 45 years STANDARD_DEVIATION 15 | 51 years STANDARD_DEVIATION 16 |
| Sex: Female, Male Female | 17 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Male | 18 Participants | 20 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 35 | 17 / 33 |
| serious Total, serious adverse events | 9 / 35 | 3 / 33 |
Outcome results
Primary
Time 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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery.
Time frame: start of administration of sugammadex to recovery from neuromuscular blockade
Population: Analysis performed using the Intent-to-Treat (ITT) Population, which consisted of all treated subjects who had at least one efficacy measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Participants With Severe Renal Impairment | Time to Recovery of the T4/T1 Ratio to 0.9. | 205 seconds |
| Participants With Normal Renal Function | Time to Recovery of the T4/T1 Ratio to 0.9. | 112 seconds |
95% CI: [36, 143]Hodges-Lehmann and Moses
Secondary
Time to Recovery of T4/T1 Ratio to 0.7
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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery.
Time frame: start of administration of sugammadex to recovery from neuromuscular blockade
Population: Analysis performed using the Intent-to-Treat (ITT) Population, which consisted of all treated subjects who had at least one efficacy measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Participants With Severe Renal Impairment | Time to Recovery of T4/T1 Ratio to 0.7 | 144 seconds |
| Participants With Normal Renal Function | Time to Recovery of T4/T1 Ratio to 0.7 | 79 seconds |
95% CI: [31, 103]Hodges-Lehmann and Moses
Secondary
Time to Recovery of the T4/T1 Ratio to 0.8
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 continued until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached at least 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery.
Time frame: start of administration of sugammadex to recovery from neuromuscular blockade
Population: Analysis performed using the Intent-to-Treat (ITT) Population, which consisted of all treated subjects who had at least one efficacy measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Participants With Severe Renal Impairment | Time to Recovery of the T4/T1 Ratio to 0.8 | 169 seconds |
| Participants With Normal Renal Function | Time to Recovery of the T4/T1 Ratio to 0.8 | 90 seconds |
95% CI: [36, 120]Hodges-Lehmann and Moses