Efficacy, Safety, and Pharmacokinetics of Sugammadex for Reversal of Neuromuscular Blockade (NMB) in Pediatric Participants (MK-8616-089)

Neuromuscular Blockade Clinical Trial

Official title:

A Phase 4 Double-Blinded, Randomized, Active Comparator-Controlled Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03351608
• Other study ID #: 8616-089
• Secondary ID: 2017-000692-92MK
• Status: Completed
• Phase: Phase 4
• Start date: February 12, 2018
• Est. completion date: January 28, 2020

Study information

• Verified date: January 2021
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial will evaluate the efficacy, safety, and pharmacokinetics of sugammadex for the reversal of both moderate and deep neuromuscular blockade (NMB) induced by either rocuronium or vecuronium in pediatric participants. The primary efficacy hypothesis of this investigation is that sugammadex is superior to neostigmine in reversing moderate NMB in pediatric participants as measured by time to recovery to a train-of-four (TOF) ratio of ≥0.9.

Description:

This trial will be conducted in two parts: Part A and Part B. In Part A, pharmacokinetic (PK) sampling will be conducted to identify the pediatric dose providing sugammadex exposure similar to adults. For Part B participants, the efficacy of sugammadex (i.e. time to recovery of the TOF ratio) 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 information / eligibility

• Status: Completed
• Enrollment: 288
• Est. completion date: January 28, 2020
• Est. primary completion date: January 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 16 Years

Eligibility

Inclusion Criteria:

• Be categorized as American Society of Anesthesiologists (ASA) Physical Status Class 1, 2, or 3.
• Have a planned non-emergent surgical procedure or clinical situation (e.g., intubation) that requires moderate or deep NMB with either rocuronium or vecuronium.
• Have a planned surgical procedure or clinical situation that would allow objective neuromuscular monitoring techniques to be applied with access to the arm for neuromuscular transmission monitoring.
• Age between 2 to <17 years at Visit 2.
• If female, may participate if she is not pregnant, not breastfeeding, and at least one of the following: 1) Not a woman of childbearing potential (WOCBP); or 2) A WOCBP who agrees to follow the study contraceptive guidance during the treatment period and for at least 7 days after the last dose of study treatment.

Exclusion Criteria:

• Has any clinically significant condition or situation (eg, anatomical malformation that complicates intubation) other than the condition being studied 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 (defined as estimated glomerular filtration rate (eGFR) <30 ml/min).
• 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.
• 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.
• Has been previously treated with sugammadex or has participated in a sugammadex clinical 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.

Related Conditions & MeSH terms

• Neuromuscular Blockade

Intervention

Drug:
• Sugammadex 2 mg/kg
For moderate NMB reversal, a single i.v. 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 TOF stimulations.
• Sugammadex 4 mg/kg
For deep NMB reversal, a single i.v. 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).
• Neostigmine + Glycopyrrolate
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 a second twitch (T2) in response to TOF stimulations.
• Neostigmine + Atropine
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 a second twitch (T2) in response to TOF stimulations.

Locations

Country	Name	City	State
Austria	Sozialmedizinisches Zentrum Ost - Donauspital ( Site 0150)	Wien
Belgium	Universitaire Ziekenhuis Antwerpen - UZA ( Site 0200)	Edegem
Belgium	UZ Leuven Campus Gasthuisberg ( Site 0201)	Leuven
Denmark	Rigshospitalet ( Site 0250)	Copenhagen
Finland	New Childrens Hospital ( Site 0750)	Helsinki
Germany	Diakovere Annastift gGmbH ( Site 0354)	Hannover
Germany	Universitaetsklinikum Giessen und Marburg GmbH ( Site 0355)	Marburg
Germany	Klinikum Rechts der Isar Technische Universitaet Muenchen ( Site 0350)	Muenchen
Germany	St. Franziskus-Hospital ( Site 0352)	Muenster
Germany	Klinikum am Steinenberg Reutlingen ( Site 0351)	Reutlingen
Germany	Josephs-Hospitals Warendorf ( Site 0353)	Warendorf
Spain	Hospital Santa Lucia ( Site 0501)	Cartagena
Spain	Hospital Universitario La Paz ( Site 0502)	Madrid
Spain	Hospital Universitario Nino Jesus ( Site 0503)	Madrid
Spain	Clinica Universitaria de Navarra ( Site 0500)	Pamplona
Turkey	Ankara Universitesi Tip Fakultesi ( Site 0551)	Ankara
Turkey	Uludag Universitesi Tip Fakultesi ( Site 0553)	Bursa
Turkey	Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 0552)	Istanbul
Turkey	Koc Universitesi Hastanesi ( Site 0555)	Istanbul
United States	C.S. Mott Children's Hospital/ University of Michigan Medical center ( Site 0014)	Ann Arbor	Michigan
United States	Duke University Medical Center ( Site 0019)	Durham	North Carolina
United States	Memorial Hermann Medical Center University of Texas Medical School ( Site 0038)	Houston	Texas
United States	Childrens Hospital Los Angeles ( Site 0030)	Los Angeles	California
United States	West Virginia University ( Site 0043)	Morgantown	West Virginia
United States	Saint Peter's University Hospital [New Brunswick, NJ] ( Site 0009)	New Brunswick	New Jersey
United States	Lucille Packard Children's Hospital ( Site 0006)	Palo Alto	California
United States	The Children's Hospital of Philadelphia ( Site 0015)	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC ( Site 0005)	Pittsburgh	Pennsylvania
United States	Rady Children's Hospital-San Diego ( Site 0035)	San Diego	California
United States	Children's National Medical Center ( Site 0008)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Denmark,  Finland,  Germany,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-Time Curve (AUC) From Dosing to Infinity (AUC0-8) of Sugammadex [Part A]	The AUCo-8 for sugammadex, defined as the area under the plasma concentration versus time plot, was determined in each Part A arm.	2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose
Primary	Plasma Clearance (CL) of Sugammadex [Part A]	The CL of sugammadex, defined as the rate of elimination relative to plasma concentration, was determined in each Part A arm.	2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose
Primary	Apparent Volume of Distribution (Vz) of Sugammadex [Part A]	The Vz of sugammadex, defined as the amount of drug administered relative to plasma concentrations, was determined in each Part A arm.	2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose
Primary	Maximum Plasma Concentration (Cmax) of Sugammadex [Part A]	The Cmax of sugammadex, defined as the maximum plasma concentration, was determined in each Part A arm.	2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose
Primary	Plasma Half-Life (t½) of Sugammadex [Part A]	The t½ of sugammadex, defined as the time required for the plasma concentration to decrease to 50% of maximum, was determined in each Part A arm.	2 minutes (min), 15 min, 30 min, 60 min, 4-6 hours (hrs), and 10 hrs post-dose
Primary	Percentage of Participants With =1 Adverse Event (AE) [Parts A and B]	The percentage of participants with =1 AE(s) for up to 7 days after treatment was determined for each treatment group, pooled according to treatment received. An AE is defined as any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated.	Up to 7 days
Primary	Time to Recovery of Participant Train-of-Four (TOF) Ratio to =0.9 [Part B]	The time to recovery of TOF ratio to =0.9 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB. Per protocol, the efficacy analysis is based on comparison of the Part B: Sugammadex 2 mg arm versus the Part B: Neostigmine + (Glycopyrrolate or Atropine) arm.	Up to 30 minutes post-dose
Secondary	Time to Recovery of Participant TOF Ratio to =0.7 [Part B]	The time to recovery of TOF ratio to =0.7 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB.	Up to 30 minutes post-dose
Secondary	Time to Recovery of Participant TOF Ratio to =0.8 [Part B]	The time to recovery of TOF ratio to =0.8 after administration of study intervention was determined for each Part B arm. The TOF ratio is the ratio of the magnitude of the fourth (T4) and first (T1) thumb twitches elicited by 4 electrical stimulations of the ulnar nerve, indicating the current degree of NMB as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Values closer to 1 indicate less NMB.	Up to 30 minutes post-dose