Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants Aged Birth to <2 Years (MK-8616-169)
- Conditions
- Neuromuscular Blockade
- Interventions
- Registration Number
- NCT03909165
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 137
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part B. Neostigmine Neostigmine + Glycopyrrolate 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, for moderate NMB reversal. Part B. Neostigmine Neostigmine + 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, for moderate NMB reversal. Part A. Sugammadex 2 mg/kg Sugammadex 2 mg/kg Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal. Part A. Sugammadex 4 mg/kg Sugammadex 4 mg/kg Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal. Part B. Sugammadex 2 mg/kg Sugammadex 2 mg/kg Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal. Part B. Sugammadex 4 mg/kg Sugammadex 4 mg/kg Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.
- Primary Outcome Measures
Name Time Method 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.
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.
- Secondary Outcome Measures
Name Time Method 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.
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Trial Locations
- Locations (39)
Lucille Packard Children's Hospital ( Site 3008)
🇺🇸Palo Alto, California, United States
Variety Children's Hospital D.B.A. Nicklaus Children's Hospital ( Site 3019)
🇺🇸Miami, Florida, United States
OU Medical Center ( Site 3005)
🇺🇸Oklahoma City, Oklahoma, United States
The Children's Hospital of Philadelphia ( Site 3021)
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh UPMC ( Site 3017)
🇺🇸Pittsburgh, Pennsylvania, United States
McGovern Medical School at UT Health/ Memorial Hermann ( Site 3014)
🇺🇸Houston, Texas, United States
University of Vermont Medical Center ( Site 3013)
🇺🇸Burlington, Vermont, United States
The Children s Hospital at Westmead ( Site 3805)
🇦🇺Westmead, New South Wales, Australia
Queensland Children s Hospital ( Site 3806)
🇦🇺South Brisbane, Queensland, Australia
Royal Childrens Hospital Melbourne ( Site 3801)
🇦🇺Parkville, Victoria, Australia
Scroll for more (29 remaining)Lucille Packard Children's Hospital ( Site 3008)🇺🇸Palo Alto, California, United States