MELAtonin for Prevention of Postoperative Agitation and Emergence Delirium in Children (MELA-PAED)

MELAtonin for Prevention of Postoperative Agitation and Emergence Delirium in Children. The MELA-PAED Trial: a Randomized, Double-blind, Placebo-controlled Trial.

Postoperative agitation and emergence delirium describe a spectrum of symptoms of early postoperative negative behavior, in which the child experiences a variety of behavioral disturbances including crying, thrashing, and disorientation during early awakening from anaesthesia. The symptoms are common with a reported incidence of approximately 25%. Some clinical trials have studied the effect of prophylactic oral melatonin for reducing the risk of emergence agitation in children, some finding a considerable dose-response effect. Melatonin has a low bio-availability of approximately 15 %. The safety of exogenous melatonin for pediatric patients has been studied with no apparent serious adverse effects, even at repeated short-term use of high doses of intravenous melatonin. The aim of this clinical trial is to investigate the prophylactic effects and safety of intravenous melatonin administered intraoperatively for prevention of postopreative agitation and emergence delirium in children after an elective surgical procedure. The study is designed as a randomised, double-blind, placebo-controlled clinical trial.

Study Overview

• Status: Not yet recruiting
• Conditions: Emergence Delirium
• Intervention / Treatment: Drug: Melatonin; Drug: Isotonic sodium chloride solution

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anne Louise B Garioud, MD; Phone Number: +4535456243; Email: anne.louise.de.barros.garioud@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 1-6 years
• Elective surgical procedure of en axpected duration of at least 30 minutes in general anesthesia maintained with sevoflurane

Exclusion Criteria:

• Any known allergy or contraindication to study treatment or excipåients
• Current daily medication with melatonin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melatonin; Participants receive melatonin solution for injection 1 mg/mL in a dosage of 0.15 mg/kg body weight as a single intravenous injection approximately 30 minutes before end of surgical procedure.	Drug: Melatonin; Melatonin for injection 1 mg/mL
Placebo Comparator: Placebo; Participants receive isotonic sodium chloride (9mg/mL) intravenously once approximately 30 minutes before end of surgical procedure in a volume equivalent to the melatonin group for the same weight.	Drug: Isotonic sodium chloride solution; Sodium chloride 0.9 % for injection; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of emergence agitation	Participants will be assessed on Watcha scale repeatedly ever 15 min during their stay at the Post-Anesthetic Care Unit. The variable is dichotomous: any score >2= "Yes" and no score <=2 = "No"	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-serious Adverse Events (AE)	Any untoward medical occurrence not considered serious.	From enrolment to the trial until 24-hour follow-up.
Opioid consumption	The total amount of opioids administered for postoperative pain in the PACU will be evaluated as units of morphine equivalents per kg. No more than 35 % of the popu-lation is expected to receive postoperative opioids in a range of approximately 10-100 µg/kg.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Adverse Events (SAE)	We will use the International Conference on Harmonization of technical require-ments for registration of pharmaceuticals for human use-Good Clinical Practice (ICH-GCP) definition of a serious adverse event, which is any untoward medical occurrence that resulted in death, was life-threatening, re-quired hospitalization or prolonging of existing hospitalization and resulted in persistent or significant disability or jeopardized the participant.	SAEs will be assessed from enrolment until 30 days after intervention.
Postoperative pain	The incidence of postoperative pain will be assessed in each group according to the FLACC scale, assessed every 15 minutes in PACU. Postoperative pain is defined as any FLACC score >3.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Postoperative nausea and vomiting (PONV)	The incidence of PONV will be assessed dichotomously every 15 minutes in PACU. Outcome assessors will observe for vomiting. Nausea can be considered present if the participant refuses to eat and other causes are ruled out. There is no adequate PONV assessment tool available. PONV will be considered present if any assess-ment during PACU stay is "Yes".	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Time for discharge readiness	Time from end of anesthesia (defined as above) to the time point at which partici-pant fulfills local discharge criteria. Discharge criteria will be evaluated by the re-sponsible physician prior to final discharge from PACU either to the participant's ward or to their home.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Time to administration of opioid	Time from end of anesthesia to the time point at which the first dose of opioid is administered in PACU. Not all participants (expectedly up to approximately 35%) will receive opioids in PACU.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Need for rescue medication	Dichotomous assessment of any administration in PACU of rescue medication specifically targeting EA according to treatment algorithm i.e., clonidine or propofol.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Time to awakening in PACU	Time from end of anesthesia to the first time point at which the participant is awake. If the participant is not awake two hours after arrival in PACU, a wake-up at-tempt will be carried out.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Time to postoperative oral intake	Time from end of anesthesia to the first time point at which the participant eats/drinks. All participants are assumed to eat/drink during their PACU stay.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Emergence delirium	The incidence of emergence delirium will be evaluated according to the PAED score assessed every 15 minutes during PACU stay. The end-point is defined dichotomously as any score ≥10. Due to feasibility concerns, this outcome will solely be evaluated in a sub-population of approximately 50% of the trial population (200 participants), specifically only thos enrolled at the Juliane Marie Center Site.	Up to approximately 4 hours corresponding to stay in Post-Anesthetic Care Unit (PACU).
Readmissions within 30 days	Assessed dichotomously counting day 0 as the day of discharge from hospital after the procedure. For the small group (expectedly <5 %) who will have had any read-missions within 30 days, the number of readmissions will be described.	From day of discharge + 30 days.

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: University of Copenhagen; Sygehus Lillebaelt; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Principal Investigator: Arash L Afshari, MD, PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 12, 2022
• First Submitted That Met QC Criteria: September 12, 2022
• First Posted (Actual): September 15, 2022

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Child; Postoperative Pain; Melatonin; Anesthesia; PONV; Sevoflurane
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Emergence Delirium; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: 20211125; 2021-006464-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No