Comparison of Neurodevelopmental Outcomes in Children Undergoing Anesthesia with Low-Dose Sevoflurane, Dexmedetomidine, and Remifentanil Versus Standard-Dose Sevoflurane

The primary objective of this study is to determine if, in children under 2 years of age undergoing **anaesthesia** expected to last 2 hours or longer, a low-dose combination of sevoflurane, dexmedetomidine, and remifentanil is superior to standard-dose sevoflurane anaesthesia. This will be assessed by evaluating the global cognitive function using the full-scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale at 3 years of age. This objective is clinically relevant as it aims to identify a potentially safer and more effective anaesthetic regimen that could minimize neurodevelopmental risks in young children.

Secondary objectives include evaluating the superiority of the low-dose anaesthetic combination over standard-dose sevoflurane in terms of: - A range of other neurodevelopmental tests at 3 years of age, including subscales of general cognitive functioning, language, executive function, memory, adaptive behaviour, clinical behaviour, and social skills. - Diagnosis of any neurodevelopmental disorder at 3 years of age. - Incidence of intra-operative hypotension and bradycardia. - Post-operative pain and time to recovery. - Pharmacokinetic/pharmacodynamic determination only in patients treated with dexmedetomidine.

The clinical trial involves a total of **300 participants** who are children under the age of 2 years, scheduled for surgery expected to last at least 2 hours. The study population includes both **male and female** subjects, and it is noted that this is a vulnerable population due to the young age of the participants. The children are generally in a state of health that allows them to undergo various types of surgeries, such as craniofacial, thoracic, abdominal, urologic, orthopaedic, and neurosurgical procedures, provided they do not meet any exclusion criteria. The selection of participants was based on their chronological age being less than 2 years and the requirement for anaesthesia lasting a minimum of 2 hours. Lifestyle considerations such as diet and physical activity are not specified, as the primary focus is on the surgical and anaesthetic conditions. The trial aims to assess the impact of low-dose sevoflurane/dexmedetomidine/remifentanil anaesthesia compared to standard dose sevoflurane anaesthesia on the global cognitive function of these children, evaluated by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale at 3 years of age.

The clinical trial is designed to evaluate the **neurodevelopmental** outcomes in children under the age of 2 years undergoing surgery lasting at least 2 hours. The trial employs a **randomized**, **double-blind**, controlled methodology to compare the effects of low-dose **sevoflurane**, **dexmedetomidine hydrochloride**, and remifentanil anesthesia against the standard dose of sevoflurane anesthesia. The primary objective is to assess the global cognitive function using the full-scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale at 3 years of age. Secondary endpoints include various neuropsychological tests, intra-operative and post-operative parameters, and safety assessments.

The trial is expected to span from September 30, 2020, to April 3, 2025. Participants will be involved in the study for a maximum treatment period of 1 day, with the anesthesia administered either via **inhalation** or **infusion**. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age and type of surgery. Follow-up visits will be scheduled to monitor cognitive and behavioral outcomes, as well as to record any adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of the primary and secondary endpoints.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for safety reasons. The trial is categorized as a Phase III clinical trial, focusing on the safety and efficacy of the anesthetic regimen in the specified pediatric population. The study does not involve any pediatric formulations, and the maximum daily and total dose amounts are specified for each anesthetic agent involved in the trial.

The clinical trial involves the use of **SEVOFLURANE**, an inhalation vapour, as an experimental medication. **Sevoflurane** is administered via the **inhalation** route. The dosage is expressed in percentage, with a maximum daily dose of 3% and a maximum total dose of 3%. The treatment period is limited to one day. **Sevoflurane** is utilized as a standard-of-care therapy in this study, serving as a comparator to evaluate the efficacy of a low-dose combination therapy. Participant compliance with the administration of **sevoflurane** is monitored throughout the trial.

**DEXMEDETOMIDINE HYDROCHLORIDE** is used as part of the experimental treatment regimen in this clinical trial. It is provided as a concentrate for solution for infusion. The administration route is **infusion**, with a dosage measured in micrograms per kilogram (µg/Kg). The maximum daily and total dose is 6 µg/Kg, with the treatment period also restricted to one day. **Dexmedetomidine hydrochloride** is combined with **sevoflurane** and **remifentanil** to form a low-dose anesthetic regimen. This combination is evaluated against the standard dose of **sevoflurane** to determine its impact on neurodevelopmental outcomes in young children. Compliance with the dosing schedule is carefully monitored to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the global cognitive function of children under 2 years of age who undergo anesthesia expected to last 2 hours or longer. The primary endpoint for efficacy is the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale, which will be assessed when the children reach 3 years of age. This assessment aims to determine if low-dose **sevoflurane** combined with **dexmedetomidine hydrochloride** and remifentanil anesthesia is superior to standard dose **sevoflurane** anesthesia.

Secondary endpoints include a range of neuropsychological tests and assessments. These include language evaluation using the Test TLV, attention and executive function assessment with the NEPSY-2 Statue Subtest, memory evaluation through NEPSY-2 Narrative Memory, and adaptive behavior assessment using the Adaptive Behavior Assessment System, 2nd Edition for ages 0-5 years. Clinical behavior will be evaluated with the Child Behavior Checklist for ages 1.5-5 years, and executive function will be assessed using the Behavior Rating of Executive Function-Preschool. Additionally, the trial will monitor anesthesia-related outcomes such as the incidence of intra-operative hypotension and bradycardia, post-operative pain using the FLACC Scale, and time to recovery. Safety will be evaluated by documenting the nature and incidence of adverse events and serious adverse events.