Neuromuscular Blockade
Conditions
Brief summary
The primary objective of this study is to explore the dose-response relation of MK-8616 (Org 25969) given as a reversal agent of Zemuron® at 1 to 2 post tetanic counts (PTCs); both Zemuron® and MK-8616 are administered by intravenous (iv) infusion. Another goal of the study is to evaluate the safety of single doses of MK-8616 administered to participants of American Society of Anesthesiologists (ASA) Physical Status Class 1 (otherwise normal, healthy participant); Class 2 (participant with a mild systemic disease); or Class 3 (participant with a severe systemic disease that limits activity, but is not incapacitating).
Interventions
DRUGMK-8616
MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.
DRUGZemuron®
Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has an ASA Class of 1 to 3 * Is scheduled for surgical procedures (excluding dental and neck surgeries) with an anticipated duration of anesthesia of ≥45 minutes with the use of Zemuron®
Exclusion criteria
* Is undergoing dental or neck surgery * Has anatomical malformation that would impede intubation * Has or is suspected to have neuromuscular disorders impairing neuromuscular block and/or significant renal 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 medications used during general anesthesia * Is pregnant * Is a female of childbearing potential not using 1 of the following methods of birth control: condom or diaphragm with spermicide, vasectomized partner (\<6 months), intrauterine device (IUD), or abstinence * Is breast-feeding * Has already participated in the study * Has participated in another clinical trial, not pre-approved by Organon Pharmaceuticals USA within 30 days of entering this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | Up to 90 minutes | The mean time from the start of MK-8616 administration to recovery T4/T1 ratio of 0.9 was determined. Less time indicates faster recovery from NMB. The ratio of T4 (fourth twitch; amplitude of fourth response to train of four \[TOF\] stimulation is expressed as percent of control T4) over T1 (first twitch; amplitude of first response to TOF stimulation is expressed as percent of control T1) ranges from 0 (complete loss of T4 twitch response) to 1.0 (complete recovery of T4 twitch response). For TOF stimulation, 4 consecutive square wave supra-maximal stimuli of 0.2 msec duration were delivered at 2 Hz every 15 seconds. Neuromuscular monitoring was performed with the TOF-Watch® SX. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | Up to 7 days following MK-8616 administration | The percentage of participants experiencing ≥1 AEs was determined. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. |
Participant flow
Recruitment details
Adult participants of American Society of Anesthesiologists (ASA) Class 1-3 who were scheduled for surgery were recruited at 4 study sites in the US.
Participants by arm
| Arm | Count |
|---|---|
| 1) Zemuron® 0.6 mg/kg + MK-8616 0.5 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 0.5 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 5 |
| 2) Zemuron® 0.6 mg/kg + MK-8616 1.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 1.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 6 |
| 3) Zemuron® 0.6 mg/kg + MK-8616 2.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 2.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 5 |
| 4) Zemuron® 0.6 mg/kg + MK-8616 4.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 4.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 3 |
| 5) Zemuron® 0.6 mg/kg + MK-8616 8.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 8.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 5 |
| 6) Zemuron® 1.2 mg/kg + MK-8616 0.5 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 0.5 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 4 |
| 7) Zemuron® 1.2 mg/kg + MK-8616 1.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 1.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 4 |
| 8) Zemuron® 1.2 mg/kg + MK-8616 2.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 2.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 4 |
| 9) Zemuron® 1.2 mg/kg + MK-8616 4.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 4.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 3 |
| 10) Zemuron® 1.2 mg/kg + MK-8616 8.0 mg/kg Participants (ASA Class 1 to 3) received an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 8.0 mg/kg iv during a single study session. MK-8616 was administered once Zemuron®-induced NMB reached 1 to 2 PTCs. | 4 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Admin. of other reversal agent | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Admin. of relaxant other than Zemuron® | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Reason not provided | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | 1) Zemuron® 0.6 mg/kg + MK-8616 0.5 mg/kg | 2) Zemuron® 0.6 mg/kg + MK-8616 1.0 mg/kg | 3) Zemuron® 0.6 mg/kg + MK-8616 2.0 mg/kg | 4) Zemuron® 0.6 mg/kg + MK-8616 4.0 mg/kg | 5) Zemuron® 0.6 mg/kg + MK-8616 8.0 mg/kg | 6) Zemuron® 1.2 mg/kg + MK-8616 0.5 mg/kg | 7) Zemuron® 1.2 mg/kg + MK-8616 1.0 mg/kg | 8) Zemuron® 1.2 mg/kg + MK-8616 2.0 mg/kg | 9) Zemuron® 1.2 mg/kg + MK-8616 4.0 mg/kg | 10) Zemuron® 1.2 mg/kg + MK-8616 8.0 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 48 Years STANDARD_DEVIATION 12 | 49 Years STANDARD_DEVIATION 10 | 52 Years STANDARD_DEVIATION 11 | 58 Years STANDARD_DEVIATION 20 | 53 Years STANDARD_DEVIATION 14 | 58 Years STANDARD_DEVIATION 11 | 47 Years STANDARD_DEVIATION 12 | 51 Years STANDARD_DEVIATION 4 | 48 Years STANDARD_DEVIATION 17 | 50 Years STANDARD_DEVIATION 10 | 51 Years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 21 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 22 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 / 5 | 0 / 6 | 0 / 5 | 0 / 3 | 0 / 5 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 5 / 5 | 6 / 6 | 3 / 5 | 1 / 3 | 4 / 5 | 4 / 4 | 4 / 4 | 4 / 4 | 2 / 3 | 2 / 4 |
| serious Total, serious adverse events | 1 / 5 | 0 / 6 | 0 / 5 | 1 / 3 | 1 / 5 | 0 / 4 | 0 / 4 | 1 / 4 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9
The mean time from the start of MK-8616 administration to recovery T4/T1 ratio of 0.9 was determined. Less time indicates faster recovery from NMB. The ratio of T4 (fourth twitch; amplitude of fourth response to train of four \[TOF\] stimulation is expressed as percent of control T4) over T1 (first twitch; amplitude of first response to TOF stimulation is expressed as percent of control T1) ranges from 0 (complete loss of T4 twitch response) to 1.0 (complete recovery of T4 twitch response). For TOF stimulation, 4 consecutive square wave supra-maximal stimuli of 0.2 msec duration were delivered at 2 Hz every 15 seconds. Neuromuscular monitoring was performed with the TOF-Watch® SX.
Time frame: Up to 90 minutes
Population: All randomized participants who received ≥1 dose of study drug, had ≥1 post baseline efficacy measurement, and did not have any important protocol violations are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1) Zemuron® 0.6 mg/kg + MK-8616 0.5 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 44.18 Minutes | Standard Deviation 34.63 |
| 2) Zemuron® 0.6 mg/kg + MK-8616 1.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 19.08 Minutes | Standard Deviation 19.98 |
| 3) Zemuron® 0.6 mg/kg + MK-8616 2.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 5.38 Minutes | Standard Deviation 5.57 |
| 4) Zemuron® 0.6 mg/kg + MK-8616 4.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 3.32 Minutes | Standard Deviation 1.63 |
| 5) Zemuron® 0.6 mg/kg + MK-8616 8.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 1.53 Minutes | Standard Deviation 0.6 |
| 6) Zemuron® 1.2 mg/kg + MK-8616 0.5 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 20.57 Minutes | Standard Deviation 0 |
| 7) Zemuron® 1.2 mg/kg + MK-8616 1.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 11.52 Minutes | Standard Deviation 11.63 |
| 8) Zemuron® 1.2 mg/kg + MK-8616 2.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 4.33 Minutes | Standard Deviation 0.52 |
| 9) Zemuron® 1.2 mg/kg + MK-8616 4.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 1.92 Minutes | Standard Deviation 0.65 |
| 10) Zemuron® 1.2 mg/kg + MK-8616 8.0 mg/kg | Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | 0.98 Minutes | Standard Deviation 0.18 |
Secondary
Percentage of Participants Experiencing ≥1 Adverse Events (AEs)
The percentage of participants experiencing ≥1 AEs was determined. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 7 days following MK-8616 administration
Population: All participants who received a dose of study treatment are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1) Zemuron® 0.6 mg/kg + MK-8616 0.5 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 100.0 Percentage of Participants |
| 2) Zemuron® 0.6 mg/kg + MK-8616 1.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 100.0 Percentage of Participants |
| 3) Zemuron® 0.6 mg/kg + MK-8616 2.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 60.0 Percentage of Participants |
| 4) Zemuron® 0.6 mg/kg + MK-8616 4.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 66.7 Percentage of Participants |
| 5) Zemuron® 0.6 mg/kg + MK-8616 8.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 80.0 Percentage of Participants |
| 6) Zemuron® 1.2 mg/kg + MK-8616 0.5 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 100.0 Percentage of Participants |
| 7) Zemuron® 1.2 mg/kg + MK-8616 1.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 100.0 Percentage of Participants |
| 8) Zemuron® 1.2 mg/kg + MK-8616 2.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 100.0 Percentage of Participants |
| 9) Zemuron® 1.2 mg/kg + MK-8616 4.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 66.7 Percentage of Participants |
| 10) Zemuron® 1.2 mg/kg + MK-8616 8.0 mg/kg | Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | 50.0 Percentage of Participants |