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

NCT03351608 | Completed Phase 4 Results DMC FDA Drug

• 3 other identifiers: 8616-0892017-000692-92MK-8616-089
• Study Type: interventional
• Target: 288
• Locations: 8 countries
• Sites: 30

Brief 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.

Conditions

Neuromuscular Blockade

Outcome Measures

Primary Outcomes (7)

• Area Under the Plasma Concentration-Time Curve (AUC) From Dosing to Infinity (AUC0-∞) of Sugammadex [Part A]

  The AUCo-∞ 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

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (2)

• Time to Recovery of Participant TOF Ratio to ≥0.7 [Part B]

  Up to 30 minutes post-dose

• Time to Recovery of Participant TOF Ratio to ≥0.8 [Part B]

  Up to 30 minutes post-dose

Study Arms (5)

Sugammadex 2 mg/kg (Part A)

EXPERIMENTAL

Single intravenous (i.v.) bolus of sugammadex at 2 mg/kg.

Drug: Sugammadex 2 mg/kg

Sugammadex 4 mg/kg (Part A)

EXPERIMENTAL

Single i.v. bolus of sugammadex at 4 mg/kg.

Drug: Sugammadex 4 mg/kg

Sugammadex 2 mg/kg (Part B)

EXPERIMENTAL

Single i.v. bolus of sugammadex at 2 mg/kg.

Drug: Sugammadex 2 mg/kg

Sugammadex 4 mg/kg (Part B)

EXPERIMENTAL

Single i.v. bolus of sugammadex at 4 mg/kg.

Drug: Sugammadex 4 mg/kg

Neostigmine (Part B)

ACTIVE COMPARATOR

Single i.v. 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).

Drug: Neostigmine + Glycopyrrolate; Drug: Neostigmine + Atropine

Interventions

Sugammadex 2 mg/kg DRUG

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.

Also known as: MK-8616, BRIDION®

Sugammadex 2 mg/kg (Part A); Sugammadex 2 mg/kg (Part B)

Sugammadex 4 mg/kg DRUG

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).

Also known as: MK-8616, BRIDION®

Sugammadex 4 mg/kg (Part A); Sugammadex 4 mg/kg (Part B)

Neostigmine + Glycopyrrolate DRUG

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 (Part B)

Neostigmine + Atropine DRUG

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.

Neostigmine (Part B)

Eligibility Criteria

• Age: 2 Years - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (30)

Childrens Hospital Los Angeles ( Site 0030)

Los Angeles, California, 90027, United States

Location

Lucille Packard Children's Hospital ( Site 0006)

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital-San Diego ( Site 0035)

San Diego, California, 92123, United States

Location

Children's National Medical Center ( Site 0008)

Washington D.C., District of Columbia, 20010, United States

Location

C.S. Mott Children's Hospital/ University of Michigan Medical center ( Site 0014)

Ann Arbor, Michigan, 48109-4245, United States

Location

Saint Peter's University Hospital [New Brunswick, NJ] ( Site 0009)

New Brunswick, New Jersey, 08901, United States

Location

Duke University Medical Center ( Site 0019)

Durham, North Carolina, 27710, United States

Location

The Children's Hospital of Philadelphia ( Site 0015)

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC ( Site 0005)

Pittsburgh, Pennsylvania, 15224, United States

Location

Memorial Hermann Medical Center University of Texas Medical School ( Site 0038)

Houston, Texas, 77030, United States

Location

West Virginia University ( Site 0043)

Morgantown, West Virginia, 26506, United States

Location

Sozialmedizinisches Zentrum Ost - Donauspital ( Site 0150)

Vienna, 1220, Austria

Location

Universitaire Ziekenhuis Antwerpen - UZA ( Site 0200)

Edegem, 2650, Belgium

Location

UZ Leuven Campus Gasthuisberg ( Site 0201)

Leuven, 3000, Belgium

Location

Rigshospitalet ( Site 0250)

Copenhagen, 2100, Denmark

Location

New Childrens Hospital ( Site 0750)

Helsinki, 00029, Finland

Location

Diakovere Annastift gGmbH ( Site 0354)

Hanover, 30625, Germany

Location

Universitaetsklinikum Giessen und Marburg GmbH ( Site 0355)

Marburg, 35043, Germany

Location

Klinikum Rechts der Isar Technische Universitaet Muenchen ( Site 0350)

München, 81675, Germany

Location

St. Franziskus-Hospital ( Site 0352)

Münster, 48145, Germany

Location

Klinikum am Steinenberg Reutlingen ( Site 0351)

Reutlingen, 72764, Germany

Location

Josephs-Hospitals Warendorf ( Site 0353)

Warendorf, 48231, Germany

Location

Hospital Santa Lucia ( Site 0501)

Cartagena, 30202, Spain

Location

Hospital Universitario Nino Jesus ( Site 0503)

Madrid, 28009, Spain

Location

Hospital Universitario La Paz ( Site 0502)

Madrid, 28046, Spain

Location

Clinica Universitaria de Navarra ( Site 0500)

Pamplona, 31008, Spain

Location

Ankara Universitesi Tip Fakultesi ( Site 0551)

Ankara, 06620, Turkey (Türkiye)

Location

Uludag Universitesi Tip Fakultesi ( Site 0553)

Bursa, 16059, Turkey (Türkiye)

Location

Koc Universitesi Hastanesi ( Site 0555)

Istanbul, 34010, Turkey (Türkiye)

Location

Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 0552)

Istanbul, 34040, Turkey (Türkiye)

Location

Related Publications (1)

• Voss T, Wang A, DeAngelis M, Speek M, Saldien V, Hammer GB, Wrishko R, Herring WJ. Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study. Paediatr Anaesth. 2022 Mar;32(3):436-445. doi: 10.1111/pan.14370. Epub 2021 Dec 17.

  PMID: 34878707 DERIVED

MeSH Terms

Interventions

Sugammadex; Neostigmine; Glycopyrrolate; Atropine

Intervention Hierarchy (Ancestors)

gamma-Cyclodextrins; Cyclodextrins; Macrocyclic Compounds; Polycyclic Compounds; Dextrins; Starch; Glucans; Polysaccharides; Carbohydrates; Phenylammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Onium Compounds; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Atropine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2017
• First Posted: November 24, 2017
• Study Start: February 12, 2018
• Primary Completion: January 28, 2020
• Study Completion: January 28, 2020
• Last Updated: February 5, 2021
• Results First Posted: February 5, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share

Locations

US (11); BE (2); TU (4); DK (1); FI (1); AU (1); DE (6); ES (4)