A DOSE-DETERMINATION STUDY OF SUGAMMADEX AS A ROCURONIUM DECURARIZATION AGENT IN CHILDREN UNDER 2 YEARS OF AGE

The primary objective is to conduct a dose-response study comparing the doses of sugammadex required to achieve complete reversal of neuromuscular block (train-of-four ratio greater than 90% assessed by electromyographic monitoring) in children under 24 months of age who received rocuronium, with the recommended adult dose of 0.6 mg/kg. This evaluation is clinically relevant for establishing appropriate dosing regimens in the pediatric population younger than 2 years, where pharmacokinetic and pharmacodynamic properties may differ significantly from adults.

The secondary objectives include:

• Comparing across three age groups (less than 6 months, 6 to 12 months, and 12 to 24 months) the sugammadex doses necessary to obtain complete decurarization, the percentage of subjects requiring doses lower than adult recommendations, and the percentage requiring higher doses than adult recommendations.

• Describing the temporal evolution of the depth of curarization during the decurarization procedure in children aged less than 24 months.

• Detecting the possible occurrence of electrical or clinical recurarization phenomena during the decurarization procedure in children aged less than 24 months and assessing their association with the initial intensity of the block, the total dose of rocuronium administered, and the time interval between the last dose of rocuronium and the first dose of sugammadex.

• Determining the incidence of recurarization, defined as reappearance of curarization after documented complete decurarization, within 60 minutes of sugammadex administration in children aged less than 24 months.

• Identifying adverse events associated with the administration of sugammadex, such as recurarization or drug hypersensitivity.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consisted of boys and girls aged less than 24 months, representing a vulnerable population group. Both male and female subjects were included in the trial. Participants were required to have an American Society of Anesthesiologists (ASA) Physical Status Class 1 or 2, indicating good to mild systemic health status. The trial enrolled pediatric patients scheduled for non-urgent non-cardiac surgical procedures or relative emergencies greater than 12 hours that necessitated curarisation with rocuronium and reversal with sugammadex. Selection criteria specified that surgical procedures must allow for neuromuscular monitoring of the adductor muscle of the thumb. Participants were required to be beneficiaries of a social security system, and informed consent was obtained from French-speaking holders of parental authority. No specific lifestyle considerations such as diet, physical activity, or habits were documented in the available trial data.

This is a **Phase IV**, open-label, dose-determination study evaluating the efficacy of **sugammadex** for the reversal of **neuromuscular blockade** induced by **rocuronium bromide** in children under 24 months of age undergoing non-cardiac surgical procedures. The study employs a **dose-response** design to determine the optimal cumulative dose of sugammadex required to achieve complete reversal of neuromuscular block, defined as a **train-of-four ratio (TOFr)** greater than 90% as assessed by **electromyographic monitoring**. Unlike the standard adult dosing regimen which utilizes a single bolus administration, this trial investigates an iterative dosing approach with multiple injections of sugammadex at 0.2 mg/kg administered cumulatively every 3 ± 1 minute until complete decurarization is achieved. The maximum daily dose of rocuronium is 0.6 mg/kg, while sugammadex is administered in incremental doses of 0.2 mg/kg with a maximum treatment period of one day for both agents.

The study population consists of boys and girls aged less than 24 months with **American Society of Anesthesiologists (ASA)** Physical Status Class 1 or 2 who are scheduled for non-urgent non-cardiac surgical procedures or relative emergencies greater than 12 hours that require neuromuscular blockade with rocuronium and subsequent reversal with sugammadex. Eligible participants must undergo surgical procedures that permit neuromuscular monitoring of the **adductor pollicis muscle**. The trial is expected to commence recruitment in September 2025 with an estimated completion date in October 2028.

The primary endpoint is the total cumulative dose of sugammadex in mg/kg required to achieve complete decurarization, defined as a train-of-four count (TOFc) of 4/4 and a TOFr of at least 90%. Secondary endpoints include comparison of the total sugammadex dose administered relative to adult population recommendations, measurements of curarization levels (TOFc and TOFr) before the first injection and after each subsequent injection of sugammadex, occurrence of **recurarization** phenomena during the decurarization procedure, intensity of initial block depth, total dose of rocuronium administered, time interval between the last administration of rocuronium and the first administration of sugammadex, occurrence of post-complete recurarization up to 60 minutes after the last sugammadex administration, and incidence of adverse events related to sugammadex administration including recurarization, respiratory events upon awakening or in the intensive care unit, and drug hypersensitivity.

Participant involvement is limited to the duration of the surgical procedure and immediate postoperative period, with neuromuscular monitoring continuing until complete reversal is documented and for up to 60 minutes thereafter to assess for potential recurarization. Early termination from the study may occur due to adverse events, protocol violations, withdrawal of parental consent, or at the discretion of the investigator if continuation is deemed not in the best interest of the participant.

This clinical trial investigates two medicinal products in pediatric patients under 2 years of age. The study employs **rocuronium bromide** as an auxiliary **myorelaxant** agent and **sugammadex** as the test investigational medicinal product for reversal of **neuromuscular blockade**.

**Rocuronium Kabi** is administered as a 10 mg/mL **solution for injection/infusion** containing rocuronium bromide as the active substance of chemical origin. The product is supplied as a solution for injection or infusion and is administered via the **intravenous route**. The maximum dose is 0.6 mg/kg body weight, with both the maximum daily dose and maximum total dose limited to 0.6 mg/kg. The treatment period is limited to 1 day. This medicinal product holds marketing authorization in Poland and is manufactured by Fresenius Kabi Polska Sp. z o.o. The **pharmaceutical form** is classified under ATC code M03AC09.

**Sugammadex Mylan** is the experimental agent administered as a 100 mg/mL solution for injection containing sugammadex as the active substance of chemical origin. This product functions as an antidote for reversal of rocuronium-induced neuromuscular block. The pharmaceutical form is a solution for injection administered via the intravenous route. The dosing regimen differs from the approved marketing authorization, as the study protocol utilizes multiple iterative injections of 0.2 mg/kg based on **train-of-four (TOF)** monitoring results, rather than the single injection approach described in the summary of product characteristics. The maximum daily dose and maximum total dose are both 0.2 mg/kg. The treatment period is limited to 1 day. This medicinal product holds European Union marketing authorization under number EU/1/21/1583/001 and is manufactured by Mylan Pharmaceuticals Limited. The product is classified under ATC code V03AB35.

The study employs **electromyographic monitoring** to assess neuromuscular function and determine the appropriate timing and dosing of sugammadex administration. The primary objective focuses on achieving complete reversal of neuromuscular blockade, defined as a **TOF ratio greater than 90%**, through dose-response evaluation in the pediatric population under 24 months of age. The dosing strategy involves administration of sugammadex based on neuromuscular monitoring parameters, specifically when recovery reaches 1-2 post-tetanic counts (PTC) or upon reappearance of T2 response, with subsequent doses titrated according to TOF measurements to ensure adequate reversal of the rocuronium-induced block.

The primary efficacy endpoint will assess the total dose of **sugammadex**, expressed in mg/kg, required to achieve complete reversal of **neuromuscular blockade**, defined as a train-of-four count (TOFc) of 4/4 and a train-of-four ratio (TOFr) of at least 90%. The total dose will be calculated by summing the cumulative sub-doses of 0.2 mg/kg administered every 3 ± 1 minute to each child until a TOFr greater than 90% is obtained. Efficacy will be evaluated through **electromyographic monitoring** to assess neuromuscular function.

Secondary efficacy assessments will include comparison of the total **sugammadex** dose administered relative to the recommended adult dose, specifically whether the dose is below or above the adult population recommendations. Measurements of **curarization levels**, including TOFc and TOFr where appropriate, will be recorded before the first injection and after each subsequent injection of sugammadex. The occurrence of **recurarization phenomena** during the decurarization procedure will be evaluated, defined as a decrease of at least 2 units in TOFc for subjects with TOFc less than 4/4 at the previous timepoint, or a decrease of at least 20% in TOFr or a return to TOFc less than 4/4 for subjects with TOFc equal to 4/4 at the previous timepoint. Additional parameters will include the intensity of initial block depth (TOFc less than 2/4 or TOFc at least 2/4), the total dose of **rocuronium** in mg/kg, and the time in minutes between the last administration of rocuronium and the first administration of sugammadex. Post-complete recurarization will be monitored up to 60 minutes after the last administration of sugammadex, defined as a measurement of TOFc less than 4/4 or TOFr less than 90% after observing a TOFr greater than 90%. Adverse events related to the administration of sugammadex, including recurarization, respiratory events on awakening or in the intensive care unit, and drug hypersensitivity, will also be assessed.