Neuromuscular Blockade
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of sugammadex (MK-8616) for reversal of both moderate and deep neuromuscular blockade (NMB) in pediatric participants aged birth to \<2 years. The primary hypothesis of this study is that sugammadex is superior to neostigmine in reversing moderate NMB as measured by time to neuromuscular recovery.
Detailed description
This trial will be conducted in two parts: Part A and Part B. In Part A, PK sampling will be conducted to identify the pediatric dose providing sugammadex exposure comparable to the next oldest age cohort. For Part B participants, the efficacy of sugammadex (i.e. neuromuscular recovery / time to extubation) will be assessed. Further, safety analyses will be conducted in both Parts A and B. Following completion of Part A, an interim analysis (IA) of the PK and safety data will be performed. Once the appropriate doses are confirmed and safety data is assessed for the 2 doses of sugammadex, then Part B will commence.
Interventions
For moderate NMB reversal, a single IV bolus of sugammadex (2 mg/kg) will be given after final dose of neuromuscular blocking agent (NMBA; rocuronium or vecuronium) and within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations.
For deep NMB reversal, a single IV bolus of sugammadex (4 mg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0).
For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as glycopyrrolate (10 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.
For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as atropine (20 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Part A will be open-label, while Part B will be double-blinded.
Eligibility
Sex/Gender
ALL
Age
1 Days to 2 Years
Healthy volunteers
No
Inclusion criteria
* Categorized as American Society of Anesthesiologists (ASA) Physical Status Class 1, 2, or 3. * Has a planned non-emergent surgical procedure or clinical situation (e.g., intubation) that requires moderate or deep NMB with either rocuronium or vecuronium. * Has a surgical procedure or clinical situation that would allow neuromuscular monitoring techniques to be applied for neuromuscular transmission monitoring. * Is male or female, between birth and \<2 years of age.
Exclusion criteria
* Is a preterm infant or neonate \<36 weeks gestational age at birth. * Has any clinically significant condition or situation (e.g., anatomical malformation that complicates intubation) other than the condition requiring the use of NMBA that, in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in the trial. * Has a neuromuscular disorder that may affect NMB and/or trial assessments. * Is dialysis-dependent or has (or is suspected of having) severe renal insufficiency. * Has or is suspected of having a family or personal history of malignant hyperthermia. * Has or is suspected of having an allergy to study treatments or its/their excipients, to opioids/opiates, muscle relaxants or their excipients, or other medication(s) used during general anesthesia. * Is expected to require mechanical ventilation after the procedure. * Has received or is planned to receive toremifene and/or fusidic acid via IV administration within 24 hours before or within 24 hours after administration of study treatment. * Use of medication expected to interfere with study treatments given in this trial. * Has been previously treated with sugammadex or has participated in a sugammadex clinical trial within 30 days of signing the informed consent form of this current trial. * Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days of signing the informed consent/assent for this current trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: Percentage of Participants With Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication | Up to Day 7 | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. As pre-specified by the protocol and SAP, the primary analysis of safety combined data across Part A and Part B (and across age cohorts) and included all AEs that occurred up to 7 days post administration of study medication. The percentage of participants with an AE was reported by treatment and dose received. |
| Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | Pharmacokinetic (PK) blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-inf for sugammadex. As pre-specified by the Statistical Analysis Plan (SAP) for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | Day 1: 2, 15, 30, and 60 minutes (1 hour) post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-1hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | Day 1: 2, 15, 30, 60, and 240 minutes (4 hours) post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-4hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Cmax for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Plasma Clearance (CL) of Sugammadex | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine CL for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Apparent Volume of Distribution (Vd) for Sugammadex | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vd for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vss for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part A: Half-Life (t1/2) of Sugammadex in Plasma | Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose | PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine t½ for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg). |
| Part B: Time to Neuromuscular Recovery (TTNMR) In Reversal of Moderate Block | Within Day 1 | Time to neuromuscular recovery was defined as the interval from administration of reversal agent to time to neuromuscular recovery. TTNMR could be assessed by 1 of 4 methods selected by the investigator, based on their judgment of what was technically feasible and clinically appropriate for the participant's procedure. These methods were inclusive of both clinical signs (head lift or hip flexion) and neuromuscular transmission monitoring using either a standard peripheral nerve stimulator or the technically challenging quantitative neuromuscular monitoring to train-of-four (TOF) ratio ≥0.9. As pre-specified by the protocol and SAP, TTNMR was analyzed only in Part B participants under the setting of moderate block for comparison of sugammadex 2 mg to neostigmine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Time to Extubation In Reversal of Moderate Block | Within Day 1 | Time to extubation was defined as the interval from administration of reversal agent to removal of the endotracheal tube. Monitoring of time to extubation during Part B (moderate block) was achieved using the Extubation Readiness Assessment, which evaluated and documented clinically relevant elements including neuromuscular recovery, mental status, return of spontaneous ventilation, adequate oxygenation, hemodynamically stabile, and core body temperature with Yes/No answers (no overall score or direction attributed). The Operating Room anesthesiologist or other trained personnel were responsible for assessing extubation readiness beginning about 1 minute after study treatment administration and reassessing every 60 seconds until time of extubation readiness was achieved. As pre-specified by the protocol, Time to Extubation was analyzed only in Part B under setting of moderate block, and Part A participants were not included in this analysis. |
Countries
Australia, Belgium, Brazil, Denmark, Finland, France, Guatemala, Hungary, Malaysia, Mexico, Netherlands, Peru, Russia, United States
Participant flow
Recruitment details
145 pediatric participants between the ages of birth and \<2 years undergoing a procedure requiring a neuromuscular blocking agent (NMBA) for either moderate or deep neuromuscular blockade (NMB) were enrolled in this study. Participants were enrolled in 4 age cohorts: birth to 27 days, 28 days to \<3 months, 3 months to \<6 months, and 6 months to \<2 years.
Pre-assignment details
50 participants were allocated to moderate block and reversal (2 mg/kg) or deep block and reversal (4 mg/kg) with sugammadex in Part A. 95 participants were randomized in Part B to moderate block and reversal (2 mg/kg) with sugammadex, deep block and reversal (4 mg/kg) with sugammadex, or moderate block and reversal with neostigmine (50 μg/kg).
Participants by arm
| Arm | Count |
|---|---|
| Part A: Sugammadex 2 mg/kg Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg. | 16 |
| Part A: Sugammadex 4 mg/kg Participants received a single IV bolus of sugammadex at 4 mg/kg. | 34 |
| Part B: Sugammadex 2 mg/kg Participants received a single IV bolus of sugammadex at 2 mg/kg. | 31 |
| Part B: Sugammadex 4 mg/kg Participants received a single IV bolus of sugammadex at 4 mg/kg. | 32 |
| Part B: Neostigmine + (Glycopyrrolate or Atropine) Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications. | 32 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Early Discharge | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Previous Drug Exposure | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Randomized By Mistake Without Study Treatment | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal By Parent/Guardian | 0 | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: Sugammadex 2 mg/kg | Part A: Sugammadex 4 mg/kg | Part B: Sugammadex 2 mg/kg | Part B: Sugammadex 4 mg/kg | Part B: Neostigmine + (Glycopyrrolate or Atropine) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 195.9 days STANDARD_DEVIATION 193.4 | 140.1 days STANDARD_DEVIATION 121.7 | 157.9 days STANDARD_DEVIATION 171.8 | 169.1 days STANDARD_DEVIATION 165.5 | 174.3 days STANDARD_DEVIATION 192.7 | 164.0 days STANDARD_DEVIATION 166.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 10 Participants | 7 Participants | 9 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 28 Participants | 21 Participants | 24 Participants | 23 Participants | 109 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| EudraCT Age Categories Infants and toddlers (28 days-23 months) | 12 Participants | 28 Participants | 24 Participants | 26 Participants | 26 Participants | 116 Participants |
| EudraCT Age Categories Newborns (0-27 days) | 4 Participants | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 29 Participants |
| Protocol-defined Age Cohorts (All Participants As Treated Population) 28 days to < 3 months | 3 Participants | 8 Participants | 6 Participants | 9 Participants | 9 Participants | 35 Participants |
| Protocol-defined Age Cohorts (All Participants As Treated Population) 3 months to < 6 months | 2 Participants | 11 Participants | 8 Participants | 8 Participants | 8 Participants | 37 Participants |
| Protocol-defined Age Cohorts (All Participants As Treated Population) 6 months to < 2 years | 6 Participants | 7 Participants | 8 Participants | 8 Participants | 9 Participants | 38 Participants |
| Protocol-defined Age Cohorts (All Participants As Treated Population) Birth to 27 days | 4 Participants | 6 Participants | 7 Participants | 6 Participants | 5 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 4 Participants | 1 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 6 Participants | 8 Participants | 8 Participants | 28 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 28 Participants | 21 Participants | 20 Participants | 17 Participants | 100 Participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 5 Participants | 11 Participants | 12 Participants | 48 Participants |
| Sex: Female, Male Male | 9 Participants | 21 Participants | 26 Participants | 21 Participants | 20 Participants | 97 Participants |
| Type of Neuromuscular Blocking Agent [NMBA] (All Participants As Treated Population) Rocuronium | 14 Participants | 25 Participants | 21 Participants | 19 Participants | 19 Participants | 98 Participants |
| Type of Neuromuscular Blocking Agent [NMBA] (All Participants As Treated Population) Vecuronium | 1 Participants | 7 Participants | 8 Participants | 12 Participants | 12 Participants | 40 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 34 | 0 / 31 | 0 / 32 | 0 / 32 |
| other Total, other adverse events | 11 / 15 | 22 / 32 | 19 / 29 | 17 / 31 | 16 / 31 |
| serious Total, serious adverse events | 1 / 15 | 1 / 32 | 3 / 29 | 1 / 31 | 0 / 31 |
Outcome results
Primary
Apparent Volume of Distribution at Steady State (Vss) for Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vss for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 1.04 Liters (L) |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 1.23 Liters (L) |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 2.07 Liters (L) |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 2.14 Liters (L) |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 1.11 Liters (L) |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 1.18 Liters (L) |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 1.69 Liters (L) |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Apparent Volume of Distribution at Steady State (Vss) for Sugammadex | 2.18 Liters (L) |
Primary
Part A: Apparent Volume of Distribution (Vd) for Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vd for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 1.14 Liters (L) |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 1.45 Liters (L) |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 2.68 Liters (L) |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 2.70 Liters (L) |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 1.22 Liters (L) |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 1.35 Liters (L) |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 2.16 Liters (L) |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Apparent Volume of Distribution (Vd) for Sugammadex | 2.77 Liters (L) |
Primary
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex
Pharmacokinetic (PK) blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-inf for sugammadex. As pre-specified by the Statistical Analysis Plan (SAP) for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 13.40 Hour (hr)*ug/mL |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 16.22 Hour (hr)*ug/mL |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 11.50 Hour (hr)*ug/mL |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 14.07 Hour (hr)*ug/mL |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 39.09 Hour (hr)*ug/mL |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 31.90 Hour (hr)*ug/mL |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 24.75 Hour (hr)*ug/mL |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex | 27.75 Hour (hr)*ug/mL |
Comparison: 2 mg/kg AUC0-inf Geometric Mean Ratio (GMR) = Birth to 27 days AUC0-inf Geometric Mean (GM) / 28 days to \< 3 months AUC0-inf GM.90% CI: [0.56, 1.21]
Comparison: 2 mg/kg AUC0-inf GMR = 28 days to \< 3 months AUC0-inf GM / 3 to \< 6 months AUC0-inf GM.90% CI: [1, 1.98]
Comparison: 2 mg/kg AUC0-inf GMR = 3 to \< 6 months AUC0-inf GM / 6 months to \< 2 years AUC0-inf GM.90% CI: [0.6, 1.11]
Comparison: 4 mg/kg AUC0-inf GMR = Birth to 27 days AUC0-inf GM / 28 days to \< 3 months AUC0-inf GM.90% CI: [0.96, 1.56]
Comparison: 4 mg/kg AUC0-inf GMR = 28 days to \< 3 months AUC0-inf GM / 3 to \< 6 months AUC0-inf GM.90% CI: [1.03, 1.62]
Comparison: 4 mg/kg AUC0-inf GMR = 3 to \< 6 months AUC0-inf GM / 6 months to \< 2 years AUC0-inf GM.90% CI: [0.7, 1.13]
Primary
Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-1hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, and 60 minutes (1 hour) post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 6.95 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 7.63 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 6.10 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 7.31 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 12.38 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 14.39 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 13.46 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex | 13.92 hr*ug/mL |
Comparison: 2 mg/kg AUC0-1hr GMR = Birth to 27 days AUC0-1hr GM / 28 days to \< 3 months AUC0-1hr GM.90% CI: [0.67, 1.23]
Comparison: 2 mg/kg AUC0-1hr GMR = 28 days to \< 3 months AUC0-1hr GM / 3 to \< 6 months AUC0-1hr GM.90% CI: [0.92, 1.69]
Comparison: 2 mg/kg AUC0-1hr GMR = 3 to \< 6 months AUC0-1hr GM / 6 months to \< 2 years AUC0-1hr GM.90% CI: [0.64, 1.08]
Comparison: 4 mg/kg AUC0-1hr GMR = Birth to 27 days AUC0-1hr GM / 28 days to \< 3 months AUC0-1hr GM.90% CI: [0.7, 1.06]
Comparison: 4 mg/kg AUC0-1hr GMR = 28 days to \< 3 months AUC0-1hr GM / 3 to \< 6 months AUC0-1hr GM.90% CI: [0.89, 1.29]
Comparison: 4 mg/kg AUC0-1hr GMR = 3 to \< 6 months AUC0-1hr GM / 6 months to \< 2 years AUC0-1hr GM.90% CI: [0.8, 1.17]
Primary
Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-4hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, and 240 minutes (4 hours) post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 10.68 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 13.99 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 10.13 hr*ug/mL |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 12.57 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 27.79 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 27.16 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 21.51 hr*ug/mL |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex | 22.43 hr*ug/mL |
Primary
Part A: Half-Life (t1/2) of Sugammadex in Plasma
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine t½ for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.84 Hours (h) | — |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.52 Hours (h) | Geometric Coefficient of Variation 20.21 |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.45 Hours (h) | Geometric Coefficient of Variation 28.57 |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.40 Hours (h) | Geometric Coefficient of Variation 24.25 |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 2.39 Hours (h) | Geometric Coefficient of Variation 27.34 |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.53 Hours (h) | Geometric Coefficient of Variation 16.42 |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.51 Hours (h) | Geometric Coefficient of Variation 28.79 |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Half-Life (t1/2) of Sugammadex in Plasma | 1.51 Hours (h) | Geometric Coefficient of Variation 19.46 |
Primary
Part A: Maximum Plasma Concentration (Cmax) of Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Cmax for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 19.59 ug/mL |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 21.18 ug/mL |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 19.39 ug/mL |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 20.99 ug/mL |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 28.56 ug/mL |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 30.38 ug/mL |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 44.51 ug/mL |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Maximum Plasma Concentration (Cmax) of Sugammadex | 40.86 ug/mL |
Comparison: 2 mg/kg Cmax GMR = Birth to 27 days Cmax GM / 28 days to \< 3 months Cmax GM.90% CI: [0.61, 1.4]
Comparison: 2 mg/kg Cmax GMR = 28 days to \< 3 months Cmax GM / 3 to \< 6 months Cmax GM.90% CI: [0.7, 1.7]
Comparison: 2 mg/kg Cmax GMR = 3 to \< 6 months Cmax GM / 6 months to \< 2 years Cmax GM.90% CI: [0.63, 1.36]
Comparison: 4 mg/kg Cmax GMR = Birth to 27 days Cmax GM / 28 days to \< 3 months Cmax GM.90% CI: [0.7, 1.26]
Comparison: 4 mg/kg Cmax GMR = 28 days to \< 3 months Cmax GM / 3 to \< 6 months Cmax GM.90% CI: [0.52, 0.89]
Comparison: 4 mg/kg AUC0-1hr GMR = 3 to \< 6 months Cmax GM / 6 months to \< 2 years Cmax GM.90% CI: [0.83, 1.43]
Primary
Part A: Plasma Clearance (CL) of Sugammadex
PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine CL for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to \<27 days, 28 days to \<3 months, 3 to \<6 months, and 6 months to \< 2 years) for each dose (2 mg and 4 mg).
Time frame: Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
Population: All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed per protocol by age cohort. One participant in the Sugammadex 2 mg/kg 3 months to \<6 months age cohort was evaluated for PK but excluded from the APaT population due to missing IV dose information. Per protocol, Part B participants were not analyzed for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Part A: Plasma Clearance (CL) of Sugammadex | 0.43 Liters/hour |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Part A: Plasma Clearance (CL) of Sugammadex | 0.66 Liters/hour |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part A: Plasma Clearance (CL) of Sugammadex | 1.28 Liters/hour |
| Part A: Sugammadex 2 mg/kg [6 Months to < 2 Years] | Part A: Plasma Clearance (CL) of Sugammadex | 1.34 Liters/hour |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part A: Plasma Clearance (CL) of Sugammadex | 0.35 Liters/hour |
| Part A: Sugammadex 4 mg/kg [28 Days to <3 Months] | Part A: Plasma Clearance (CL) of Sugammadex | 0.61 Liters/hour |
| Part A: Sugammadex 4 mg/kg [3 to < 6 Months] | Part A: Plasma Clearance (CL) of Sugammadex | 0.97 Liters/hour |
| Part A: Sugammadex 4 mg/kg [6 Months to < 2 Years] | Part A: Plasma Clearance (CL) of Sugammadex | 1.27 Liters/hour |
Primary
Part B: Time to Neuromuscular Recovery (TTNMR) In Reversal of Moderate Block
Time to neuromuscular recovery was defined as the interval from administration of reversal agent to time to neuromuscular recovery. TTNMR could be assessed by 1 of 4 methods selected by the investigator, based on their judgment of what was technically feasible and clinically appropriate for the participant's procedure. These methods were inclusive of both clinical signs (head lift or hip flexion) and neuromuscular transmission monitoring using either a standard peripheral nerve stimulator or the technically challenging quantitative neuromuscular monitoring to train-of-four (TOF) ratio ≥0.9. As pre-specified by the protocol and SAP, TTNMR was analyzed only in Part B participants under the setting of moderate block for comparison of sugammadex 2 mg to neostigmine.
Time frame: Within Day 1
Population: All randomized participants in Part B who received ≥1 dose of study treatment for moderate NMB reversal (i.e. Sugammadex 2 mg/kg or Neostigmine + \[Glycopyrrolate or Atropine\]) and with available TTNMR data were analyzed. Per the protocol objective, no formal test for efficacy with comparison to neostigmine was done for Part A and Part B deep block, thus Part A and Part B 4 mg/kg participants were not included in this analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part B: Time to Neuromuscular Recovery (TTNMR) In Reversal of Moderate Block | 1.4 Minutes | 95% Confidence Interval 1.1 |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part B: Time to Neuromuscular Recovery (TTNMR) In Reversal of Moderate Block | 4.4 Minutes | 95% Confidence Interval 2.7 |
Comparison: The Hazard Ratio (HR) for the pairwise comparison of Sugammadex 2 mg/kg vs. Neostigmine + (Glycopyrrolate or Atropine) was based on a Cox regression model with Efron's method of tie handling with covariates of treatment, age (continuous) and stratified by neuromuscular blocking agent.p-value: =0.000295% CI: [1.37, 4.18]Log Rank
Primary
Parts A and B: Percentage of Participants With Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. As pre-specified by the protocol and SAP, the primary analysis of safety combined data across Part A and Part B (and across age cohorts) and included all AEs that occurred up to 7 days post administration of study medication. The percentage of participants with an AE was reported by treatment and dose received.
Time frame: Up to Day 7
Population: All enrolled/randomized participants from both Part A and Part B (combined per protocol) who received at least 1 dose of study treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Sugammadex 2 mg/kg [Birth to 27 Days] | Parts A and B: Percentage of Participants With Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication | 68.2 Percentage of Participants |
| Part A: Sugammadex 2 mg/kg [28 Days to <3 Months] | Parts A and B: Percentage of Participants With Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication | 68.3 Percentage of Participants |
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Parts A and B: Percentage of Participants With Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication | 61.3 Percentage of Participants |
Comparison: The difference in percentage of participants with an AE in sugammadex 2 mg/kg group versus the Neostigmine + (Glycopyrrolate or Atropine) group was based on the Miettinen and Nurminen method stratified by neuromuscular blocking agent and age group.95% CI: [-14.2, 29.5]
Comparison: The difference in percentage of participants with an AE in sugammadex 4 mg/kg group versus the Neostigmine + (Glycopyrrolate or Atropine) group was based on the Miettinen and Nurminen method stratified by neuromuscular blocking agent and age group.95% CI: [-13.5, 26.7]
Secondary
Part B: Time to Extubation In Reversal of Moderate Block
Time to extubation was defined as the interval from administration of reversal agent to removal of the endotracheal tube. Monitoring of time to extubation during Part B (moderate block) was achieved using the Extubation Readiness Assessment, which evaluated and documented clinically relevant elements including neuromuscular recovery, mental status, return of spontaneous ventilation, adequate oxygenation, hemodynamically stabile, and core body temperature with Yes/No answers (no overall score or direction attributed). The Operating Room anesthesiologist or other trained personnel were responsible for assessing extubation readiness beginning about 1 minute after study treatment administration and reassessing every 60 seconds until time of extubation readiness was achieved. As pre-specified by the protocol, Time to Extubation was analyzed only in Part B under setting of moderate block, and Part A participants were not included in this analysis.
Time frame: Within Day 1
Population: All randomized participants in Part B who received ≥1 dose of study treatment for moderate NMB reversal (i.e. Sugammadex 2 mg/kg or Neostigmine + \[Glycopyrrolate or Atropine\]) were analyzed. Per the protocol objective, no formal test for efficacy with comparison to neostigmine was done for Part A and Part B deep block, thus Part A and Part B 4 mg/kg participants were not included in this analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: Sugammadex 2 mg/kg [3 to < 6 Months] | Part B: Time to Extubation In Reversal of Moderate Block | 7.9 Minutes | 95% Confidence Interval 5.7 |
| Part A: Sugammadex 4 mg/kg [Birth to 27 Days] | Part B: Time to Extubation In Reversal of Moderate Block | 10.5 Minutes | 95% Confidence Interval 7.9 |