Use of remimazolam for pediatric sedation

Abstract

This application relates to a method for sedating a pediatric subject by intravenous administration of remimazolam or a pharmaceutically acceptable salt thereof to the subject. The disclosure relates to a method for sedating a pediatric subject during a procedure, the method comprising the step of intravenously administering to the subject a besylate of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazole[1,2-a][1,4]benzodiazepine-4-yl]-propionate methyl ester of formula (I) (remimazolam).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 519,082, filed on August 11, 2023, which is incorporated herein by reference in its entirety.

Background Art

[0002] Sedation during pediatric procedures is mainly performed for painless procedures outside the operating room. The above sedation should be performed by specialized staff with experience and training in the management of cardiorespiratory depression in children.

[0003] Both IV and non - IV administration routes are used in pediatric procedural sedation, but the IV route is always preferred when possible, especially when maximum efficiency and throughput are desired (e.g., emergency imaging procedures for diagnostic purposes). Rapid and predictable onset of action means that dosing is easier and recovery is potentially faster. In addition, in the event of inappropriate sedation or serious adverse events, the absence of IV access may prevent further management.

[0004] Drugs used for sedation during painless pediatric procedures include dexmedetomidine, etomidate, midazolam, propofol, ketamine, clonidine, and short - acting barbiturates (pentobarbital, methohexital). For longer - term procedural sedation (e.g., MRI scanning), propofol or dexmedetomidine are the most commonly used sedatives. Both drugs are effective, but there are some safety drawbacks. Propofol is associated with more airway interventions or IV fluid administration, and dexmedetomidine is associated with significant bradycardia, especially in infants.

[0005] Remimazolam (CNS7056) is a benzodiazepine developed as an ultrashort-acting intravenous (IV) sedative for use in adults undergoing procedural sedation, general anesthesia, and in intensive care units. Sedation is initiated with a single bolus dose of 0.05–0.075 mg / kg remimazolam in healthy young adults, with onset observed within 1–2 minutes. Induction of mild to moderate sedation is associated with a plasma level of approximately 0.2 mcg / mL. Loss of consciousness occurs at doses of 0.1 mg / kg (elderly) or 0.2 mg / kg (healthy young adults) and is associated with a plasma concentration of approximately 0.65 mcg / mL. Depth, duration, and recovery of sedation are dose-dependent. The time to full awakening is approximately 10 minutes for 0.075 mg / kg of remimazolam.

[0006] Like other benzodiazepines, remimazolam is associated with cardiovascular and respiratory events (e.g., hypotension, bradycardia, apnea, and hypoxia). Respiratory depression (decreased respiratory rate and / or breath volume) is usually temporary and resolved by stimulating the patient or by reducing the dose of the sedative. Oxygen may be required to restore hemoglobin oxygen saturation. Cardiovascular depression (decreased heart rate and / or blood pressure) is common but usually not serious and does not usually require treatment. Suppression of vital signs can often be inferred from the dose of remimazolam administered and is not observed as frequently as with midazolam or propofol. Airway obstruction is a common consequence of suppression of consciousness (i.e., consciousness is present or sedation is deeper than minimal sedation). It occurs when the tongue obstructs the pharynx or when secretions are not swallowed and accumulate in the pharynx. If left untreated, hypoxia can develop within 20-30 seconds, and even faster in young children and infants. A minority of airway interventions, such as jaw lift, oropharyngeal airway insertion, or secretion removal, are usually required. Children have narrower airways and larger tonsils and adenoids, which can increase the risks associated with sedation and make life-saving airway management more difficult than in adults. Autonomic nervous system activity may also be higher, increasing the risk of arrhythmias and vagal responses compared to adults.

[0007] Remimazolam is approved by the U.S. Food and Drug Administration for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less, but its safety and efficacy for sedation in patients under 18 years of age have not yet been established. While there is much known about the use of remimazolam in adults, that information is generally not transferable to sedation in pediatric patients for several reasons. Sedation in pediatric patients for procedures differs from that in adults in several ways. For example, adults may only require mild to moderate sedation to complete a procedure, while pediatric subjects typically require deeper sedation to successfully complete the procedure. In addition, procedures that can be performed in 30 minutes or less in adults often require longer than 30 minutes in children. Furthermore, the level of sedation in adults with remimazolam has been validated using the 6-point Modified Observer's Alertness / Sedation Scale (MOAA / S). In contrast, the 5-point University of Michigan Sedation Scale (UMSS) is considered more appropriate for monitoring pediatric sedation because applying adult sedation data to pediatric patients can be confusing.

[0008] The pharmacodynamics of remimazolam in children are unclear. For example, the clearance of remimazolam in neonates may be slower than in adults because CES1 is less abundant in neonates than in adults, resulting in lower enzyme activity. While changes in clearance do not enhance the sedative effect of remimazolam (i.e., do not produce deeper levels of sedation), reduced clearance may prolong its effects, potentially leading to changes in top-up dosing and / or recovery time.

[0009] The adverse event profile of remimazolam in pediatric subjects is unknown, and paradoxical reactions have been reported in children after benzodiazepine treatment. While agitation and delirium TEAEs were not observed in clinical trials of remimazolam for procedural sedation in adults, the incidence of agitation and delirium TEAEs was 11.1% in clinical trials for deeper sedation (e.g., general anesthesia) with remimazolam.

[0010] There is a need for methods to safely and effectively use remimazolam for sedation in pediatric populations. [Overview of the project] [Means for solving the problem]

[0011] concise summary This disclosure relates to a method for sedating a pediatric subject during a procedure, wherein the method comprises methyl ester of formula (I) 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazole[1,2-a][1,4]benzodiazepine-4-yl]-propionate (remimazolam) [ka] The present invention relates to a method comprising the step of intravenously administering the besylate of the above-mentioned subject.

[0012] These and other purposes and benefits shall be evident from the attached drawings and their descriptions.

[0013] The accompanying drawings (which are incorporated herein by reference and constitute part thereof) illustrate embodiments and, together with the general description set forth above and the detailed descriptions of embodiments set forth below, are useful in illustrating the principles of this disclosure. [Brief explanation of the drawing]

[0014] [Figure 1]Figure 1 is a graph showing a computer model of the steady-state pharmacodynamic interaction between fentanyl and remimazolam. See Example 2. Expected probabilities of UMSS = k and k ∈ {0,1,2,3} for various remimazolam-fentanyl combinations according to the pharmacodynamic model. The calculated remimazolam effect-site concentration driving the pharmacodynamic effect is shown on the x-axis. Background fentanyl regimens are represented as expected effect-site concentrations and shown by different line types: co-administration without fentanyl (solid black line), 1 ng.mL-1 (dashed black line), 2 ng.mL-1 (solid red line), and 4 ng.mL-1 (dashed red line). The range of expected remimazolam effect-site concentrations from this study is indicated by shaded regions.

[0015] [Figure 2] Figure 2 is a flowchart illustrating the administration of both bolus and infusion dosing regimens targeting various sedation levels and opioid requirements. All dose calculations should be rounded to two decimal places for patients with body weight <25 kg and to one decimal place for patients with body weight ≥25 kg. For this trial, opioids should not be administered 60 to 5 minutes before the start of remimazolam. For this trial, an opioid bolus may be administered during the procedure; an additional remimazolam bolus should not be given within 2 minutes after the opioid dose. An opioid bolus should not be administered within 2 minutes of the remimazolam bolus.

[0016] [Figure 3]Figure 3 is a diagram illustrating the timing of administration and PK sampling in relation to safety and PD assessment between bolus regimens. *After the start of the procedure; **Not necessary if a second or fourth remimazolam bolus is not administered during the procedure; ***Post-procedure testing is required simultaneously with the final PK sample. If PK sampling is not intended or performed after the completion of the above procedure, post-procedure testing may be performed at any time after the procedure before the patient is ready for discharge. Vital signs (temperature, mean non-invasive blood pressure, heart rate, respiratory rate, SpO2). Each remimazolam bolus should be spaced at least 3 minutes apart (from the start of one bolus to the start of the next). The eighth PK sample may be from children aged 6 to under 18 years in Cohort 1.

[0017] [Figure 4] Figure 4 is a diagram illustrating the timing of administration and PK sampling in relation to safety and PD assessment during the infusion regimen. **Not required if the procedure lasts less than 15 minutes. The fourth scheduled PK sample is taken at 30 minutes, but this PK sampling point may be omitted if the procedure is expected to be completed within 5 minutes. ***Post-procedure testing is required simultaneously with the final PK sample. If PK sampling is not intended or performed after the completion of the procedure, the post-procedure testing may be performed at any time after the procedure before the patient is ready to leave the room. Vital signs (temperature, mean non-invasive blood pressure, heart rate, respiratory rate, SpO2). Additional remimazolam boluses should be spaced at least 3 minutes apart (from the start of one bolus to the start of the next). The eighth PK sample may be from children aged 6 to under 18 years in Cohort 1. [Modes for carrying out the invention]

[0018] Detailed explanation In the present disclosure, the singular forms “a,” “an,” and “the” include plural references, and a reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to “a material” includes at least one of such materials and their equivalents known to those skilled in the art.

[0019] When a value is presented as an approximation by use of the descriptor “about,” it is understood that the particular value forms another embodiment. In general, the use of the term “about” indicates an approximation that may vary depending on the desired characteristics to be obtained by the disclosed subject matter and should be interpreted in the context in which it is used based on its function. Those skilled in the art will also interpret this as a matter of convention. In some cases, the number of significant digits used with respect to a particular value may be one non-limiting way of determining the degree of the word “about.” In other cases, the steps used in a series of values may be used to determine the intended range available for the term “about” with respect to each value. All ranges, if present, are inclusive and combinable. That is, a reference to a value stated within a range includes all values within that range.

[0020] When a list is presented, it should be understood that each individual element of that list and any combination of that list should be construed as a separate embodiment unless otherwise stated. For example, a list of embodiments presented as “A, B, or C” should be construed to include the embodiments “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0021] For clarity, it should be recognized that certain features of the invention described herein in the context of separate embodiments may also be provided in combination within a single embodiment. That is, each individual embodiment is considered to be combinable with any other embodiment, unless clearly incompatible or excluded, and such combinations are considered to be another embodiment. Conversely, for brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any partial combination.Further noted is that the claims may be drafted to exclude alternative elements. Thus, this statement is intended to serve as a preamble for the use of exclusive terminology such as "solely", "only", etc. in the recitation of claim elements, or the use of "negative limitations". Finally, an embodiment may be described as part of a series of steps or a more general structure, but each of the above steps may also be considered an independent embodiment in itself.

[0022] The terms "subject" and "patient" are used interchangeably and refer to a human. In some embodiments, the human is a pediatric, i.e., less than 18 years old.

[0023] "Treating" or variations thereof refer to eliminating or reducing at least one physical parameter of the disease or disorder. In other embodiments, "treating" refers to modulating the disease or disorder, either physically (e.g., by stabilizing recognizable symptoms) or physiologically (e.g., by stabilizing physical parameters), or both. In further embodiments, "treating" refers to delaying the onset of the disease or disorder.

[0024] This disclosure relates to a method for safely and effectively sedating pediatric patients with remimazolam or a pharmaceutically acceptable salt thereof, e.g., remimazolam besylate. When used herein, pediatric patients are considered to be sedated within the scope of this disclosure when the patient's sedation is determined to be approximately 2–3 on the University of Michigan Sedation Scale (UMSS), e.g., 2–3. In some cases, the patient is considered to be sedated within the scope of this disclosure when the patient's sedation is a UMSS score of 2. In some cases, the patient is considered to be sedated within the scope of this disclosure when the patient's sedation is a UMSS score of 3. In other cases, the patient is considered to be sedated within the scope of this disclosure when the patient's sedation is determined to be approximately 2 on the Nurse Interpretation Sedation Score (NISS), e.g., 2.

[0025] Pediatric patients may be sedated using the methods described herein for procedures lasting approximately 2 hours or less. In some cases, the procedures may last approximately 2.5 hours, 2 hours, 1.5 hours, or 1 hour. In other cases, the procedures may last less than 1 hour, for example, 45 minutes, 30 minutes, or 15 minutes. These procedures may include, for example, endoscopic procedures, lumbar punctures, bone marrow aspirations, imaging procedures (e.g., X-ray, MRI, computed tomography (CT), interventional radiography), dental procedures, painful dressing changes, postoperative procedures requiring sedation, cardiac catheterization, or central venous catheter insertion. Other appropriate procedures include nerve blocks, central venous catheter removal, and conscious intubation. Procedures performed using the sedation methods described herein are successfully completed without the need for any rescue sedatives.

[0026] According to the method described, the pediatric subject is administered an initial dose of remimazolam or a pharmaceutically acceptable salt thereof. Preferably, the remimazolam is administered as remimazolam besylate. In preferred cases, the initial dose is a bolus dose. The initial bolus dose is in the range of about 100 micrograms / kg (mcg / kg) to about 500 mcg / kg. The doses described herein are based on remimazolam free base. The molecular weight of remimazolam free base is 439.3 g / mol. The molecular weight of remimazolam besylate is 597.5 g / mol. A person skilled in the art administering remimazolam besylate can easily calculate the equivalent dose of remimazolam free base.

[0027] In several scenarios, the pediatric subjects are administered an initial bolus dose of remimazolam besylate at a concentration of 100 mcg / kg of remimazolam free base. In other contexts, the pediatric subjects are administered an initial bolus dose of remimazolam besylate in amounts of 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mcg / kg of remimazolam free base. In a favorable scenario, the pediatric subject is administered an initial bolus dose of remimazolam besylate in the amount of remimazolam free base at 200 mcg / kg.

[0028] The initial bolus dose described above should be administered over a period of 5 minutes or less, for example, over approximately 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute. In some cases, the initial bolus dose should be administered over a period of less than 1 minute or less than 30 seconds. Preferably, the initial bolus dose should be administered over a period of approximately 1 to 2 minutes, for example, over 1 to 2 minutes. More preferably, the initial bolus dose should be administered over a period of approximately 1 minute, for example, over 1 minute.

[0029] After the pediatric subject has received the initial bolus dose, the subject may be further administered one or more supplemental doses of remimazolam free base or remimazolam besylate. Any one or more supplemental doses are administered at least approximately 3 minutes after the initial bolus dose.

[0030] The above-mentioned at least one or more supplemental doses may be administered as a bolus, sequentially, or as a combination of a bolus and a sequential dose. According to this disclosure, each of the above one or more supplemental doses is administered after the initial bolus dose. In some cases, one or more supplemental doses are administered before the commencement of the procedure. In some cases, one or more supplemental doses are administered during the procedure. In some cases, at least one supplemental dose is administered before the commencement of the procedure. In other cases, no supplemental doses are administered before the commencement of the procedure. In some cases, at least one supplemental dose is administered during the procedure. In other cases, no supplemental doses are administered after the commencement of the procedure. In some cases, one or more supplemental doses are administered before the commencement of the procedure, and one or more doses are administered during the procedure.

[0031] Preferably, the above 1 or more supplemental doses are of remimazolam besilate. In some cases, the pediatric subject is administered one supplemental dose of remimazolam besilate. In some cases, the pediatric subject is administered two supplemental doses of remimazolam besilate. In some cases, the pediatric subject is administered three supplemental doses of remimazolam besilate. In some cases, the pediatric subject is administered four supplemental doses of remimazolam besilate. In some cases, the pediatric subject is administered five supplemental doses of remimazolam besilate. In some cases, the pediatric subject is administered six supplemental doses of remimazolam besilate. In some cases, the pediatric subject is administered seven supplemental doses of remimazolam besilate. In some cases, the pediatric subjects are administered eight supplemental doses of remimazolam besilate. In some cases, the pediatric subjects are administered nine supplemental doses of remimazolam besilate. In some cases, the pediatric subjects are administered ten supplemental doses of remimazolam besilate. Preferably, the pediatric subjects are administered supplemental doses between 1 and 5 of remimazolam besilate. In some cases, the pediatric subjects are not administered any supplemental dose of remimazolam besilate.

[0032] According to this disclosure, the administration of any supplemental dose is preceded by an interval of at least about 1 minute from any previous supplemental dose. In some cases, the administration of any supplemental dose is preceded by an interval of at least about 1 minute, 1.5 minutes, 2 minutes, 2.5 minutes, 3 minutes, or 3.5 minutes from any previous supplemental dose. In preferred cases, the administration of any supplemental dose is preceded by an interval of at least about 3 minutes, for example, 3 minutes, from any previous supplemental dose. By example, if two supplemental doses are administered, the second supplemental dose is administered at least 3 minutes after the first supplemental dose. Also by example, if three supplemental doses are administered, the third supplemental dose is administered at least 3 minutes after the second supplemental dose. Also by example, if four supplemental doses are administered, the fourth supplemental dose is administered at least 3 minutes after the third supplemental dose. Also by example, if five supplemental doses are administered, the fifth supplemental dose is administered at least 3 minutes after the fourth supplemental dose.

[0033] In some aspects of this disclosure, one or more of the above supplemental doses may be administered as a bolus dose. In those aspects, the above supplemental dose of remimazolam besylate is approximately 100 mcg / kg to approximately 300 mcg / kg of remimazolam free base. In some aspects, the above supplemental bolus dose of remimazolam besylate is 100, 200, or 300 mcg / kg of remimazolam free base. In some aspects, the above supplemental bolus dose of remimazolam besylate is 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mcg / kg of remimazolam free base. In favorable circumstances, the supplemental bolus dose of remimazolam besylate is approximately 200 mcg / kg of free remimazolam base, for example, 200 mcg / kg.

[0034] In other aspects of this disclosure, one or more of the above supplemental doses may be administered as a continuous intravenous dose after the initial bolus dose. One or more of the above supplemental doses administered as a continuous intravenous dose are administered at least about 3 minutes after the initial bolus dose. According to this disclosure, one of the above supplemental bolus doses may be administered over a period of 5 minutes or less, for example, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute. In some aspects, the supplemental bolus dose may be administered over a period of about 1 to 2 minutes, for example, 1 to 2 minutes. In some aspects, the supplemental bolus dose may be administered over a period of less than 1 minute or less than 30 seconds.

[0035] When the supplement dose is administered as a continuous intravenous dose, the infusion rate is between approximately 0 mcg / kg / min and approximately 80 mcg / kg / min of remimazolam free base during the remainder of the procedure described above. For example, when the supplement dose is administered as a continuous intravenous dose, the infusion rate is approximately 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 This could be 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 90 mcg / kg / min of remimazolam free base.

[0036] In some situations where the supplemental dose is administered as a continuous intravenous dose, the infusion dose may be increased. In those situations, the infusion dose is increased in stages. In some situations, the infusion dose is increased in stages by 10 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is increased in stages by 15 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is increased in stages by 20 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is increased in stages by 25 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is increased in stages by 30 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is increased in stages by 35 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 40 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 45 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 50 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 55 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 60 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 65 mcg / kg / min of remimazolam free bases. In some situations, the infusion dose is gradually increased by 70 mcg / kg / min of remimazolam free bases. In some cases, the infusion dose is increased stepwise by 75 mcg / kg / min of remimazolam free bases. In some cases, the infusion dose is increased stepwise by 80 mcg / kg / min of remimazolam free bases. According to this disclosure, any stepwise increase is preceded by an interval of at least about 1 minute, for example, about 1 minute, 1.5 minutes, 2 minutes, 2.5 minutes, 3 minutes, or 3.5 minutes. In some cases, any stepwise increase is preceded by an interval of at least about 3 minutes, for example, 3 minutes. [Examples]

[0037] Example 1 Primary objective: To evaluate the efficacy of IV remimazolam in inducing and maintaining appropriate levels of sedation in pediatric patients undergoing diagnostic and / or therapeutic procedures.

[0038] Primary endpoint: Successful procedure defined as all of the following: The procedure is complete, and No need for rescue sedatives, There is no need for remimazolam bolus / infusion regimens exceeding what is permissible.

[0039] Successfully performing the procedure without any rescue sedatives indicates that the sedative effect of remimazolam is satisfactory. A similar primary endpoint, used in a phase 3 clinical trial in adults, was accepted by the FDA and EMA as appropriate for approval of remimazolam for procedural sedation in adults.

[0040] Secondary objective: To evaluate the action onset and elimination characteristics, safety, and pharmacokinetic properties of IV remimazolam in pediatric patients undergoing diagnostic and / or therapeutic procedures, and to establish dose levels for different age groups.

[0041] Secondary efficacy endpoint: - Target depth of sedation to be achieved (The target depth of sedation on UMSS is predetermined for each patient based on the procedure, and the patient requires it before the procedure.) - The target range of sedation achieved during 80% of the procedure duration (i.e., UMSS 2-3) - Percentage of time within the target range of sedation between procedures - Appropriateness of sedation as evaluated over time as NISS - Target sedation level and time to procedure initiation after the first dose of remimazolam [minutes] - Time to full wakefulness after the end of the procedure and the last dose of remimazolam (defined as the first of three consecutive UMSS score 0s) [minutes] - Signs of resedation, i.e., whether a UMSS score > 0 was observed during the time between the completion of the procedure and the patient's departure from the room after reaching UMSS 0. - Time [minutes] to become suitable for discharge after the completion of the procedure and the last dose of remimazolam. - Success of the procedure, excluding cases where the procedure could not be completed for reasons other than sedation. Defined as all of the following: - Completion of the procedure, - No need for rescue sedatives, - No need for remimazolam bolus or infusion regimens exceeding what is permissible.

[0042] Secondary safety endpoints: Adverse events (TEAEs) that occurred during treatment after initiation of remimazolam Vital signs (heart rate, mean non-invasive blood pressure, body temperature, respiratory rate, and SpO2) The need for any manual or mechanical ventilation (including mask ventilation without LMA / IGEL / ETT insertion) Reasons for use / indications for the reversal agent flumazenil, including its necessity. Delirium during recovery from the completion of the procedure until the patient is ready to leave the room (Pediatric Anesthesia Recovery Delirium Scale).

[0043] PK rating: After initiating remimazolam, PK sampling is performed for PK data analysis. This PK data is then graphically displayed against the predicted PK from the PK / PD model for each age group. The appropriateness of the predicted dose is assumed if the individually obtained values ​​fall within the confidence limits of the prediction (intravenous concentrations 1 minute and 5 minutes after the first dose).

[0044] Because the Revised Observer Awakening / Sedation (MOAA / S) scale (used in the adult Phase 3 remimazolam trial) is unreliable in children, the UMSS and NISS were selected for this trial. The UMSS has been reported to be a simple, effective, and reliable tool that facilitates rapid and frequent assessment and recording of sedation depth in children. It was also used in the dexmedetomidine Major PICU trial evaluated by the EMA. In addition, the NISS will be used for secondary endpoints as recommended by the PDCO. Maximum sedation depth will be pre-defined individually for each patient, taking into account diverse patient characteristics and needs, as well as the different durations and invasiveness of procedures in this trial. At least 80% of the procedure duration elapsed within the target sedation range is considered sufficient to reflect the sedation-maintaining effect of remimazolam.

[0045] The action onset and recovery profile of remimazolam will be evaluated using time-to-event endpoints. The above action onset and recovery profile reflects the efficacy of remimazolam as an ultrashort-acting sedative.

[0046] The need for the antagonist flumazenil indicates an overdose of remimazolam and is evaluated as a secondary safety endpoint.

[0047] Since respiratory depression and hemodynamic changes are class effects of benzodiazepines, vital signs and the need for airway intervention will be evaluated as secondary safety endpoints.

[0048] Childhood awake delirium is a phenomenon whose significance and risk factors are not fully understood. Awake agitation is reported in up to 18% of children aged 3–7 years. Another study reported post-anaesthetic excitement in 13% of children aged 3–9 years and 9% of children aged 10–19 years. Volatile anesthetics, type of surgery, parent / patient anxiety, patient's pre-existing behaviors, and other factors such as patient / parent-healthcare provider interactions may contribute to childhood awake delirium. Therefore, awake delirium will be monitored during the recovery phase in this trial.

[0049] As this trial is the first in the overall pediatric development program, it will derive the doses that will be used across all age groups for different indications. It will also be a trial in the least vulnerable patients (who are generally healthier compared to patients in planned general anesthesia and ICU sedation trials), as well as a trial with short exposure and relatively low doses. The initial dose / dosing regimen for this trial will be predicted based on target concentrations from the adult trial. Therefore, it is essential to assess the accuracy of these predictions through PK sampling and, if necessary, adapt the dosing for subsequent younger age groups. The PK results of this trial will also inform whether the pharmacodynamics of remimazolam differ in children, i.e., whether children in a given age group exhibit the same level of sedation as adults at a given plasma concentration.

[0050] Given the small number of patients per age group, as well as the predictable variability of different procedures and flexible medications, sparse sampling or population PK approaches are not feasible. Sample size calculations based on typical variability in the PK model resulted in minimum sample sizes of 20 patients aged 6 to under 18 years (Cohort 1) and 20 patients aged 3 to under 6 years (Cohort 2). In conclusion, if the minimum requirement for PK samples per cohort is met, PK sampling of the remaining patients within that cohort may not be essential.

[0051] Clinical trial design

[0052] This is a Phase 2 / 3 clinical trial evaluating the efficacy, safety, and pharmacokinetics of remimazolam for intravenous sedation in pediatric patients undergoing diagnostic and / or therapeutic procedures.

[0053] The maximum duration of the trial for any patient is 28 days; patients are screened within 21 days prior to the start of the procedure, and follow-up contact takes place 4 days (+3 / -1 day) after the procedure.

[0054] For each patient, one of two different medication regimens may be selected depending on the procedure and the patient's needs; The medication is administered as an initial bolus, followed by one or more additional boluses if necessary. The medication is administered as an initial bolus, followed by a series of infusions that can be adjusted to the required depth of sedation.

[0055] Approximately half of the patients enrolled in the above study received an initial bolus and additional regimens, and half of those patients received an initial bolus followed by a series of infusion regimens.

[0056] The above clinical trial will begin with a partial set of patients from Cohort 1 (ages 12 to under 18) with at least the first five patients, then proceed to the remaining patients in Cohort 1, and subsequently to the younger age group (Cohort 2).

[0057] In total, we will recruit at least 100 patients: Cohort 1: Ages 6 to under 18 (at least 40 patients; of which at least 30 are between 6 and under 12 years old) Cohort 2: Ages 3 to under 6 (n=35).

[0058] Doses for age groups 6 to under 18 years and 3 to under 6 years, targeting moderate to deep sedation (UMSS score 2-3) with opioid premedication, were simulated using a remimazolam PK / PK model that uses adult criteria for remimazolam 5 mg targeting moderate sedation with opioid premedication.

[0059] Clinical trial design and development Medication regimen 1

[0060] Doses for age groups 6 to under 18 years and 3 to under 6 years, targeting moderate to deep sedation (UMSS score 2–3) with opioid premedication, were simulated using a PK / PD model for remimazolam, employing adult criteria for 5 mg of remimazolam targeting moderate sedation with opioid premedication. In adults, the initial dose of remimazolam targeting moderate sedation without opioids is 7 mg; therefore, the initial dose for moderate to deep sedation (UMSS score 2–3) without opioids was increased. The initial dose for mild to moderate sedation (UMSS score 1–2) with or without opioids was 50% of the dose for moderate to deep sedation (UMSS score 2–3) with or without opioids, respectively. Additions were set to 50% of the above initial bolus, consistent with the previous dosing regimen.

[0061] Alternatively, a drug regimen including an initial bolus followed by continuous infusions may be used for prolonged and invasive procedures, based on the patient's needs. For adults, the standard dose, an initial dose of 5 mg with opioid premedication to achieve moderate sedation, was used to maintain a target plasma concentration of 200 ng / mL, ranging from 100 to 300 ng / mL, while achieving moderate to deep sedation (UMSS score 2-3) with concurrent opioid administration, simulating an infusion rate of 3.5 mcg / kg / min.

[0062] Infusion therapy may be more convenient than bolus administration. Pediatric anesthesiologists may prefer this method of administration for certain procedures (e.g., imaging techniques).

[0063] Medication regimen 2

[0064] As part of a pediatric research program agreed upon with the US FDA, a clinical trial was initiated in 2021 to evaluate the efficacy and safety of IV remimazolam in inducing and maintaining sedation in pediatric patients undergoing diagnostic and / or therapeutic procedures. See Example 2. Model-based optimization of the above dosing regimen was performed using preliminary pharmacokinetic and pharmacodynamic analyses of remimazolam. Thirty-one patients (6–18 years old) were included in the trial and stratified across four treatment arms: repeated bolus administration, sequential infusion and repeated bolus administration, repeated bolus + fentanyl co-administration or sequential infusion, and repeated bolus + fentanyl co-administration. The above patient data were reviewed after dosing of the first five patients (three of whom received the above infusion regimen, and two received the above bolus and additional regimen). Three patients required rescue sedatives to complete the procedure; therefore, the above dosing regimen was reconsidered. The above data suggested that the sedation levels observed in pediatric patients were consistent with those observed in adults for the given doses; that is, moderate sedation corresponds to MOAA / S levels 2–3 in adults and UMSS 2 in children. However, it was clear that the investigators required a somewhat deeper level of sedation (i.e., UMSS 3) for children to minimize movement between procedures. Therefore, to facilitate this deeper sedation, both the initial bolus and starting infusion doses were increased for the procedure, corresponding to a target UMSS score of 2–3. In addition, the maximum permissible infusion dose was harmonized across different drug regimens to a level consistent with that shown to be safe in adults. In the above patients requiring rescue sedatives, the target sedation was never achieved. This suggests that the 50% additional dose did not increase plasma concentrations beyond those achieved by the initial bolus. Therefore, flexibility was introduced into the trial design so that the additional bolus would be 50-100% of the initial bolus, allowing for a deeper sedation level if it was inappropriate for the child's needs after the initial bolus.

[0065] Medication regimen 3

[0066] Efficacy and PK data were reviewed after 31 pediatric subjects (see Example 2 below) completed Cohort 1. It was noted that the efficacy of the above drug regimen 2 was not optimal. PK / PD analysis revealed that the PK was as expected, i.e., the initial dose of the above drug regimen produced the target plasma concentration range. However, even after exceeding the target plasma concentration range with an additional bolus dose, or even after increasing the infusion rate to a higher acceptable range, UMSS 3 could not be reliably achieved. This was particularly true for children weighing 47 kg or more, i.e., those for whom upper limits were set on the bolus and infusion doses. Therefore, the above drug regimen was modified again based on the PK / PD model designed from the data of the first 31 enrolled children.

[0067] Based on the information collected and analyzed from drug regimens 1, 2, and 3, the trial design was developed by incorporating the following changes: The medication regimen focused solely on moderate to deep sedation, i.e., UMSS levels 2–3. The majority of patients recruited so far required UMSS level 2 or 3. Therefore, mild sedation was excluded, and medication focused only on moderate to deep sedation. Regarding the initial and additional bolus doses, previous dose limits, which were implemented as part of adult medication regimens, were removed, particularly because children who had dose limits required rescue sedation. The intensity of the initial bolus dose was increased from 150 mcg / kg to 200 mcg / kg because the majority of patients required multiple bolus doses before achieving the target UMSS score. For the same reason, the intensity of the additional bolus was set to the same intensity as the initial bolus, i.e., to reduce the number of doses and the time before the procedure began. In line with this, the duration of the additional bolus administration was increased to 1 minute (i.e., to have the same duration of administration for the same dose). For maintaining adequate sedation, an additional bolus of half the initial intensity is still possible. The initial infusion rate and the acceptable range were increased because numerous additional boluses were needed between infusions to achieve / maintain the target level of sedation. Bolus doses were introduced before each increase in infusion rate, but boluses were not permitted during infusions at a constant rate. Specific medication instructions for patients receiving fentanyl have been removed because fentanyl is used at low doses, and the level of synergistic sedative effect is lower than perceived. Furthermore, fentanyl is used purely to provide analgesia during painful procedures.

[0068] The medication regimens are shown in Table 4. [Table 4]

[0069] Clinical trial group

[0070] Inclusion criteria

[0071] A pediatric patient may be included in the clinical trial if he / she meets all of the following inclusion criteria: 1. There is a signed informed consent and agreement form (if applicable), and the patient and parent are willing to participate in the clinical trial. 2. At a US facility Male or female patients aged 3 to under 18 years are scheduled to undergo medically indicated and unrelated diagnostic or treatment procedures. 3. Maximum planned duration of the procedure: 2 hours 4. ASA Physical Condition I-III 5. Spontaneous breathing is expected during sedation. 6. Women who are of potential pregnancy (i.e., post-menarche) and sexually active must use highly effective contraception throughout the trial period (from consent until completion of all research procedures). This includes: Intrauterine system or device Hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings, or long-acting injections). 7. For women who may be pregnant (i.e., after menarche), a negative pregnancy test is required at the time of screening and on the day of treatment. If screening is performed on the same day as treatment, one test is sufficient. 8. Procedures targeting UMSS level 2-3 sedation

[0072] exclusion criteria Pediatric patients who meet any of the following criteria will be excluded from participating in this clinical trial: 1. Emergency Procedures 2. Conditions / procedures requiring planned airway control via endotracheal tube or LMA insertion. 3. Craniofacial deformities that are likely to significantly limit the possibility of emergency airway rescue. 4. Other airway-related abnormalities that may interfere with emergency airway rescue (including enlarged tonsils and anatomical abnormalities of the upper or lower airway). 5. Known hypersensitivity to any of the following components of a drug product: benzodiazepine, flumazenil, dextran, or remimazolam. 6. Known paradoxical reactions to benzodiazepines 7. History of sleep apnea 8. Active respiratory failure 9. Active neuromuscular diseases 10. Active heart failure 11. Active liver failure 12. Pregnant or breastfeeding women 13. Contraindicated drugs: • If any investigational drug other than remimazolam is taken within 30 days prior to the treatment date or with a half-life of less than 7 (whichever is longer) • Any drug other than remimazolam administered for sedation purposes (except for the use of nitrous oxide to facilitate IV cannula placement, which is permitted). • Clonidin • Lactated Ringer's solution or acetate Ringer's solution administered together with remimazolam using the same intravenous line. 14. Any patient deemed unsuitable for the clinical trial for any other reason. 15. Your body mass index (BMI) relative to your age percentile is equal to or higher than the 95th percentile.

[0073] Recruitment

[0074] Patients requiring medically indicated procedures (within 2 hours) for sedation with or without local / IV analgesia may be enrolled. These procedures are expected to differ across age groups. Similarly, the following examples are listed according to age group:

[0075] Ages 6 to under 18: Endoscopy lumbar puncture Bone marrow aspiration Imaging method Dental Procedures Painful bandage changes and other postoperative procedures involving sedation Cardiac catheterization Central venous catheter insertion

[0076] Ages 3 to under 6: Endoscopy lumbar puncture Imaging method Dental Procedures Painful bandage changes and other postoperative procedures involving sedation Cardiac catheterization Central venous catheter insertion

[0077] Investigational drug

[0078] Medication and administration

[0079] Two different medication regimens can be chosen: If necessary, administer an initial remimazolam bolus, followed by additional boluses. The initial remimazolam bolus, followed by continuous infusions, can be adjusted to the desired depth of sedation.

[0080] The medication regimen to be used is determined for each patient before the start of administration. Continuous infusions are likely to be used for procedures lasting more than 30 minutes. In addition, the selection of the medication regimen may be based on priority and the patient's accessibility (for example, additional medication may be difficult during an MRI scan).

[0081] If pain is anticipated during the procedure, local anesthesia and / or analgesics are permissible according to local standards.

[0082] Medication and administration in the age group of 6 to under 18 years old (Cohort 1)

[0083] Table 4 (above) provides an overview of dosages for both bolus and infusion dosing regimens targeting different sedation levels and opioid requirements.

[0084] Figure 2 shows a flowchart illustrating the administration of both bolus and infusion drug regimens targeting different sedation levels and opioid requirements.

[0085] Figure 3 illustrates the timing of administration and PK sampling related to safety and PD assessment between bolus regimens.

[0086] Figure 4 illustrates the timing of administration and PK sample administration related to safety and PD assessment between infusion regimens.

[0087] Initial bolus and subsequent medication:

[0088] A bolus dose (200 mcg / kg) is administered manually by IV injection over approximately 1 minute. If sedation is insufficient to initiate the procedure after the initial dose, one or more additional doses (200 mcg / kg) may be administered as boluses at intervals of at least 3 minutes (from the start of one bolus to the start of the next). If the procedure has been initiated, adequate sedation may be maintained with further additional boluses of 100–200 mcg / kg if necessary. Considering the synergistic effects of opioids, the frequency of additional doses should be adjusted to an appropriate depth of sedation while maintaining a 3-minute interval between additional doses. With respect to at least a 3-minute interval, the frequency of additional doses should be adjusted to the desired depth of sedation, taking into account the synergistic effects of opioids. If the desired level of sedation cannot be achieved or maintained within any 15-minute range, it is suggested that the remimazolam drug product be discontinued and an alternative rescue sedative be used. The choice of the rescue sedative to be used is at the discretion of the physician. If significant hemodynamic instability and / or respiratory compromise occurs based on clinical judgment, even without excessive sedation, measures should be taken immediately to address these conditions (e.g., use of intravenous fluid, use of vasopressors, and / or use of anticholinergics). In addition, the above bolus and additional doses, as well as / or frequency of administration, may be reduced.

[0089] Medication with initial bolus and infusion:

[0090] The initial bolus of remimazolam (200 mcg / kg) is administered manually by IV injection over approximately 1 minute. This is followed by a continuous infusion (10 mcg / kg / min) starting after the completion of the initial bolus. If signs of awakening or insufficient sedation are observed, administer another bolus, followed by an increase in the infusion rate to 20 mcg / kg / min. Further increases to 40 mcg / kg / min first, and finally to 80 mcg / kg / min, are possible if necessary. Each increase in the infusion rate follows the remimazolam bolus (200 mcg / kg). There should be at least a 3-minute interval between the start of one bolus and the start of the next. The dose level should be adjusted to the desired depth of sedation, taking into account the synergistic effect with opioids. If the desired level of sedation cannot be achieved or maintained within any 15-minute range, it is suggested that remimazolam be discontinued and an alternative rescue sedative be used. The choice of rescue sedative to be used is at the discretion of the doctor.

[0091] If sedation becomes too deep, the infusion may be temporarily stopped. After the procedure has started, the above infusion dose may be modified at the discretion of the patient between 0 and 80 mcg / kg / min to maintain the ideal level of sedation. A 3-minute interval should be maintained between each increase in the infusion rate. If sedation decreases to less than UMSS 2 during the procedure, a bolus (200 mcg / kg) should be administered before increasing the infusion rate.

[0092] If significant hemodynamic instability and / or respiratory dysfunction occurs based on clinical judgment, even without excessive sedation, measures should be taken immediately to address these conditions (e.g., via intravenous fluid bolus, use of vasopressors, and / or use of anticholinergics). In addition, infusion may be reduced or discontinued, or the frequency or dose of additional boluses may be reduced.

[0093] Medication and administration in the age group of 3 to under 6 years old (Cohort 2)

[0094] Medication regimens for the age group 6 to under 18 years may be used for the younger age group 3 to under 6 years. This is because the PK modeling simulates the age range 3 to under 18 years, and the remimazolam dose described for 6 to under 18 years is also suitable for maintaining target plasma concentrations in children aged 3 to under 6 years. All dose calculations should be rounded to two decimal places for patients weighing less than 25 kg, and to one decimal place for patients weighing 25 kg or more.

[0095] Opioid administration

[0096] Some procedures (e.g., endoscopy, lumbar puncture, bone marrow aspiration, some dental procedures, and painful bandage changes) may require opioid analgesia, including fentanyl. In addition, opioid analgesia may be required for positioning during imaging procedures.

[0097] Opioid-induced analgesia is expected to be synergistic with remimazolam. Opioids should not be administered 60 to 5 minutes before the start of remimazolam administration (T=0). An opioid bolus may be administered during the above procedure, but an additional remimazolam bolus should not be given within 2 minutes after the opioid dose. Conversely, an opioid bolus should not be administered within 2 minutes of the remimazolam bolus.

[0098] Fentanyl administration:

[0099] Fentanyl remains one of the most widely used opioids in children receiving sedation, and a great deal of clinical experience exists regarding its use. The pharmacokinetics of co-administration of remimazolam and fentanyl from adult procedural sedation studies, along with clinical experience, were used to determine the range of fentanyl doses to be used in the aforementioned studies. [Table 5]

[0100] Fentanyl boluses may be administered every 5 minutes if necessary, but additional fentanyl boluses should not be given within 2 minutes of a remimazolam bolus. In addition, remimazolam boluses should not be given within 2 minutes of a fentanyl bolus. A patient is considered to have exceeded the maximum dose of fentanyl if administered at doses exceeding 3 mcg / kg / hour. If adequate analgesia cannot be achieved with the doses highlighted above, consider using an alternative analgesia, or consider discontinuation if it is due to inadequate analgesia.

[0101] Local anesthesia / IV pain loss

[0102] If pain is anticipated during the procedure, local anesthesia and / or analgesics are permissible according to local standards.

[0103] Nitrous oxide for IV cannula placement

[0104] To facilitate IV cannula placement, nitrous oxide may be administered according to local practice. A minimum of 10 minutes must elapse between the discontinuation of N2O administration and the initiation of remimazolam administration. Alternatively, EtN2O should be less than 5% before the initiation of remimazolam administration. Ensure and record in the medical record that the patient has returned to baseline levels of sedation before initiating remimazolam administration.

[0105] Rescue sedatives

[0106] Rescue sedatives are defined as any drug other than remimazolam that is given to initiate or continue a procedure by either inducing or maintaining an appropriate level of sedation. Rescue sedatives are therefore given when adequate sedation with remimazolam cannot be induced or maintained. Rescue sedatives should be administered when the maximum dose and dosing regimen of remimazolam specific to the patient's age group described above has not induced or maintained adequate sedation for the procedure. The procedure may then be continued, at the discretion of the pediatrician, with any other sedative suitable for pediatric use (e.g., midazolam, propofol, dexmedetomidine) or reorganized at another time.

[0107] Concomitant drugs

[0108] Except for contraindicated drugs, all other concomitant medications may be administered during the above procedure. However, compatibility studies for most concomitant medications and remimazolam are not available; therefore, they should not be administered concurrently with remimazolam.

[0109] During the remimazolam infusion regimen, concomitant medications, with the exception of some of the maintenance fluid, must be administered via PK cannula.

[0110] Between remimazolam bolus and additional regimens, concomitant drugs may be administered via the PK cannula or the same cannula used for remimazolam administration, but the two drugs will not be co-administered.

[0111] Contraindicated drugs

[0112] The following medications are prohibited until the patient is deemed suitable for discharge after eligibility has been confirmed. Any drug other than remimazolam administered for sedative purposes (apart from the use of nitrous oxide to facilitate IV cannula placement, which is permissible). Chlonidine Lactated Ringer's solution or acetate Ringer's solution administered together with remimazolam using the same intravenous line. Other investigational drugs besides remimazolam Opioid drugs 60 to 5 minutes before starting remimazolam

[0113] Inappropriate sedation / analgesia

[0114] It is recognized that the above-mentioned patients may encounter situations where they cannot be sedated to a level considered appropriate for the procedure being performed. Therefore, the procedure may need to be discontinued. Similarly, the procedure may also need to be discontinued if there is insufficient analgesia, even if they may be receiving adequate sedation.

[0115] Signs of inappropriate sedation may include: The patient is awake and responds to voices. Persistently low UMSS or NISS scores

[0116] Signs of inappropriate loss of pain include: Patient discomfort or injury due to a lack of cooperation or adverse physiological or psychological responses to stress. high blood pressure Tachycardia

[0117] In events requiring the termination of a procedure, all post-procedures and follow-up procedures should be carried out in accordance with the protocol.

[0118] Formulation of the remimazolam investigational drug product: The chemical name of remimazolam besylate is 4H-imidazole[1,2-a][1,4]benzodiazepine-4-propionic acid, 8-bromo-1-methyl-6-(2-pyridinyl)-(4S)-,methyl ester, benzenesulfonate (1:1). All doses and concentrations in this protocol are expressed as base, remimazolam unless otherwise specified.

[0119] Remimazolam besylate drug products are sterile, preservative-free, white to grayish-white lyophilized powders in 12 mL vials. The composition of the contents in each vial is shown in the table below. Store in a light-protected place between 15°C and 25°C. [Table 6]

[0120] preparation

[0121] Remimazolam drug products need to be reconstituted with a sterile 0.9% NaCl solution to obtain an injectable solution with a concentration of 1.0 mg / mL.

[0122] Clinical trial evaluation and procedures

[0123] Effectiveness evaluation The level of sedation is assessed over time using the University of Michigan Sedation Scale (UMSS; Table 7). The timing of the assessment is defined herein. [Table 7]

[0124] The appropriateness of sedation is assessed over time using the Nurse Sedation Interpretation Score (NISS; Table 8). The timing of the assessment is defined herein. [Table 8]

[0125] PK sampling

[0126] Venous plasma samples are collected as outlined herein. Each sample volume is 300 μL of blood, and a maximum of 7 samples (n=8 for the age group 6 to under 18 years) are collected for PK analysis. The total volume of blood sampled during the trial for PK purposes is 2.1 mL (2.4 mL for the age group 6 to under 18 years).

[0127] PK sampling during MRI procedures is preferable but not mandatory.

[0128] Safety evaluation Physical examination: including at least the cardiovascular, respiratory, and any other systems suspected of having pathology. A urine pregnancy test (HCG) was administered as a dipstick to all female participants who were potentially pregnant (i.e., those who had not yet had their first menstruation). Measure the mean non-invasive blood pressure. For designated patients, leave the measuring device in the same location on the day of treatment.

[0129] ASA Physical Condition Classification (Table 9) [Table 9]

[0130] Post-sedation agitation should be assessed using the Pediatric Awakening Delirium of Epilepsy (PAED) Scale (Table 10) from the end of the procedure until the patient is ready to leave the recovery room. [Table 10]

[0131] Adverse events and serious adverse events

[0132] Definition of Adverse Events (AEs)

[0133] An adverse event (AE) is defined as any undesirable medical event in a clinical trial subject that is not necessarily causally related to the treatment. Therefore, an AE may be any undesirable and unintentional sign (including clinically significant abnormal values ​​from relevant tests (e.g., clinical safety laboratory tests, ECG, vital signs), symptoms, or illnesses that are time-related to the use of remimazolam), whether or not they are thought to be related to remimazolam.

[0134] A clinically significant abnormality is one that is symptomatic and requires discontinuation of remimazolam, additional diagnosis, or treatment.

[0135] Definition of serious adverse events

[0136] A SAE is defined as any adverse medical event or effect occurring in a subject in a clinical trial administered a pharmaceutical product that may or may not be causally related to the treatment, and which is serious (i.e., resulting in death, life-threatening, requiring hospitalization or extension of current hospitalization, resulting in persistent or significant disability or incapacity, or a birth defect or congenital defect) or otherwise medically significant (i.e., potentially endangering the subject or requiring intervention to prevent one of the above characteristics / outcomes). SAEs include all serious events, regardless of whether or not there is suspected causal link to remimazolam.

[0137] Definition of serious adverse reactions (SARs)

[0138] A serious adverse reaction (SAR) is any adverse and unintentional response to remimazolam that is related to any dose administered and, at any dose, results in death, is life-threatening, requires hospitalization or extension of current hospitalization, causes lasting or significant disability or incapacity, is a birth defect or birth defect, or is otherwise medically significant (potentially endangering the subject or requiring intervention to prevent one of the above characteristics / consequences). This suggests a reasonable possibility of a causal relationship between the event and remimazolam, i.e., evidence suggesting causality.

[0139] A "suspected" SAR refers to an individual SAE case report from a clinical trial in which a causal relationship between SAE and remimazolam was suspected. All individually reported SARs are considered suspect.

[0140] Definition of an unexpected adverse reaction

[0141] An unexpected adverse reaction is defined as an adverse reaction (AR) whose nature or severity does not match the applicable product information (e.g., the IB for an unapproved investigational product or the product characteristics summary for an approved product).

[0142] A suspected unexpected serious adverse reaction (SUSAR) is an SAR that occurs in a clinical trial and is not included in the list of expected SARs in IB (unexpected).

[0143] Classification of adverse events

[0144] Severity of the event

[0145] Severity is assessed using the following three categories: Mild: The event requires minimal intervention or no intervention is required, and does not interfere with the participant's daily activities. Moderate: The event causes a low level of inconvenience or concern with the treatment. A moderate event may cause some interference with function. Severe: The event interferes with the participant's normal daily activities and may require systemic medication or other treatment. Severe events are usually life-threatening or may result in incapacitation. It should be noted that the term “severe” is not necessarily equivalent to “serious.”

[0146] For all test values ​​outside the normal range, a severity grading system will be evaluated.

[0147] Relationship with investigational drugs

[0148] To classify the suspected association between AE and remimazolam, the following binary system of causal evaluation will be used: Related: There is a reasonable possibility that remimazolam caused the adverse event. Irrelevant: There is no reasonable possibility that remimazolam causes adverse events.

[0149] "Reasonable possibility" means that there is evidence suggesting a causal relationship between remimazolam and adverse events.

[0150] Outcome

[0151] The outcomes of AE are classified as follows: Resolved: The above patient has fully recovered and no symptoms remain. Resolved but with lingering effects: The above patient recovered, but some symptoms remain. Resolving: The patient's condition is improving, but symptoms remain. Unresolved: The patient's condition has not improved, and their symptoms are unchanged or worsening. Death (Death should only be selected as an outcome if death results from an AE. If more than one AE may be associated with the patient's death, the outcome of death should be indicated for each such AE.)

[0152] Adverse events of special interest (AESI)

[0153] Any clinically significant changes in vital signs or the need for manual or mechanical ventilation, if likely related to remimazolam, should be reported as an AESI. These will be analyzed separately: Decreased oxygen saturation: Hypoxia is defined as SpO2 < 92% or below 5% of preoperative baseline for more than 1 minute, or any decrease requiring intervention; Clinically relevant bradycardia: Heart rate below the absolute (1st percentile) value for each age group as shown in Table 11; defined as a decrease of 35% or more from the baseline value recorded at screening in heart rate ≥. Hypotension: Defined according to Table 11 Respiratory depression (the values ​​for defining respiratory depression as an AESI by age category can be found in Table 11); Mask ventilation, LMA / IGEL, or any manual or mechanical ventilation via an endotracheal tube.

[0154] AESI will be monitored and recorded from the start of remimazolam until the patient is deemed suitable for discharge. [Table 11] * Based on the definition of bradycardia in the studies of Larsson et al. (Larsson, PG, et al., Incidence of bradycardia at arrival to the operating room after oral or intravenous premedication with clonidine in children. Paediatr Anaesth., 2015. 25: p. 956-962), Mason and Loenqvist (Mason, KP and Loenqvist, P.-A, Bradycardia in perspective—not all reductions in heart rate need immediate intervention. Paediatr Anaesth., 2015. 25: p. 44-51), the definition of bradycardia has been modified to reflect the definition in the study of Fleming et al. (Fleming, S., et al, Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet, 2011. 377: A value below the first percentile identified in the study (pp. 1011-1018) is defined as bradycardia. **Following the definition of hypotension proposed in Nafiu et al. (Nafiu, OO, et al. How do pediatric anesthesiologists define intraoperative hypotension? Paediatr. Anaesth., 2009. 19: p. 1048-1053). *** Modified from the definition of bradypnea in Fleming et al. (Fleming, S., et al, Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet, 2011. 377: p.1011-1018).

[0155] Analysis of the primary efficacy endpoint

[0156] Primary objective: To evaluate the efficacy of intravenous remimazolam in inducing or maintaining an appropriate level of sedation in pediatric patients undergoing diagnostic and / or therapeutic procedures.

[0157] The primary objective is evaluated using the following primary endpoint variables and their measurement levels (Table 12). [Table 12]

[0158] The primary endpoint consists of all three components. The primary endpoint is met when (i.e., when the treatment is considered successful for the patient): Procedure complete = Yes, and No need for rescue sedatives = Yes, and No need for remimazolam bolus / infusion regimens exceeding what is permitted = Yes.

[0159] Analysis of secondary endpoints

[0160] Secondary objective: To evaluate the action onset and elimination characteristics, safety, and pharmacokinetics of IV remimazolam in pediatric patients undergoing diagnostic or therapeutic procedures, and to establish dose levels in different age groups.

[0161] The following table outlines the variables used to establish secondary objectives and their measurement levels (Table 13). [Table 13] * Details regarding the equipment used in this table can be found in Section 8.0 and subsequent sections concerning efficacy measurement and safety evaluation. ** Ranking may be displayed based on response patterns. *** Further PK analysis will be described in a separate PK SAP.

[0162] In the table above, the 5-point scale is considered at interval levels, yielding reports of the mean and standard deviation for each scale or subscale. However, where a 3-point or 4-point scale is observed, due to the expected limited sample size in cohort-based analyses, its values ​​are treated essentially as ordinal.

[0163] All measurements recorded in a single occurrence are reported as mean ± standard deviation or as counts and percentages within a category, depending on the statistical level of the variable. All reports for these variables are arranged sequentially based on the time the evaluations occur. Since most scales are administered only once, the effectiveness of primary and secondary objectives is based on this reporting. Currently, there are no thresholds for the effectiveness of the scales or variables used, and no statistical tests are planned.

[0164] All categories of serious adverse events are reported in a separate table after the completion of the clinical trial for each registered age group.

[0165] PK analysis

[0166] The sedation level (as clinically defined) is C max , C x , C tau AUC x We compare the PK parameters against those of other available time points (where x is another available time point). The results of the PK analysis are presented in both tabular and graphical formats across applicable time points.

[0167] Example 2: PK / PD Modeling Study Methods: Thirty-one patients aged 6 to 18 years were included in the clinical trial. Patients were stratified into four treatment arms: repeated bolus administration, continuous infusion and repeated bolus administration, repeated bolus + fentanyl co-administration or continuous infusion, and repeated bolus + fentanyl co-administration. See the table below. [Table 1] [Table 2]

[0168] Sedation levels were assessed using the University of Michigan Sedation Scale. Blood samples were collected and measured for remimazolam and CNS7054 (the major metabolite of remimazolam). Population pharmacokinetic modeling was performed using NONMEM®. Dosage regimen and power / sample size calculation optimization were performed using R®.

[0169] We developed a co-population pharmacokinetic model describing the concentration-time profiles of remimazolam and CNS7054 (a remimazolam metabolite) in the absence and presence of fentanyl. Size-adjusted representative PK parameters were similar to those previously reported in adults. A proportional odds logistic regression PD model, combined with a simplified Minto model assuming an additive interaction between remimazolam and fentanyl, well described the observed UMSS. The steady-state exposure-response relationship following this model is shown in Figure 1. Clinical trial simulations indicated that the drug regimens tested in a 31-subject trial were unlikely to provide adequate sedation in the majority of patients. According to the PK / PD model, a more appropriate dosing regimen would consist of a higher remimazolam bolus dose per kg (200 mcg.kg-1 vs. 150 mcg.kg-1) and infusion rate (up to 80 mcg.kg-1.min-1 instead of 20 mcg.kg-1.min-1), an expanded dose setting scheme for continuous infusions (10-80 mcg.kg-1.min-1 instead of 7.5-20 mcg.kg-1.min-1), shorter dose intervals for additional bolus doses (at least 2 minutes between bolus doses vs. 3 minutes), removal of the maximum dose limit that was based on adult dosing, and more frequent fentanyl co-administration at higher (per kg) bolus doses (2 mcg.kg-1 vs. 1 mcg.kg-1). Clinical trial simulations suggest that a trial involving 30 patients aged 3 to under 18 years receiving this more appropriate drug regimen has a high probability of showing that more than 70% of the patients achieve UMSS ≥ 3 15 minutes after the first remimazolam bolus dose.

[0170] This modeling study suggests that the pharmacokinetics of remimazolam may not differ between children aged 6 years and older and adults (after adjusting for body size differences). While pharmacodynamics may differ between children and adults, this difference may be partly (or entirely) due to the fact that a deeper level of sedation is desirable for children compared to adults in terms of treatment-time sedation. The exposure-response relationship suggests that the drug regimen studied in the above 31-subject clinical trial is insufficient to meet the primary endpoint identified in the protocol. Higher remimazolam exposure is required for effective use of remimazolam for treatment-time sedation in children aged 6 years and older.

[0171] This disclosure is illustrated by describing several embodiments, the illustrative embodiments of which are described in considerable detail, but it is not the applicant's intention to limit or otherwise restrict the appended claims to such detail. Additional advantages and modifications may be readily apparent to those skilled in the art. Furthermore, features from separate lists may be combined; features from examples may be generalized to the entire disclosure.

[0172] List of Abbreviations Adverse events (AEs) AESI (Adverse Events of Special Interest) ASA (American Society of Anesthesiologists) Area under the AUC curve BMI (Body Mass Index) BP (Blood Pressure) beats per minute CES1 Carboxylesterase-1A CONSORT: Integrated standards for reporting clinical trials DMC Data Monitoring Committee ECG (Electrocardiogram) eCRF Electronic Case Report Form EMA (European Medicines Agency) EtCO2 (End-tidal CO2) EtN2O End-tidal nitrous oxide EU (European Union) FDA (U.S. Food and Drug Administration) FPFV / FPI: First patient's first visit / first patient registration GCP (Good Clinical Practice) IB Investigational Drug Summary ICF Informed Consent Form ICH International Conference on Harmonisation of Regulation of Pharmaceuticals for Human Use IEC Independent Ethics Committee IMP Investigational Drug Products IV Intravenous IxRS Interactive Response System LMA / IGEL / ETT Laryngeal mask airway / IGEL / Endotracheal tube LPLV / LPO: Last patient's last visit / last patient registration MedDRA Glossary of Pharmaceutical Regulatory Terms NISS Nurse Sedation Interpretation Scale NRS (Numerical Rating Scale) PAED (Pediatric Anesthesia Recovery) Delirium PD Pharmacodynamics PIP: Pediatric Investigation Plan PK (Pharmacokinetics) SAE (Serious Adverse Event) SAP Statistical Analysis Plan SAR (Serious Adverse Reaction) SOP (Standard Operating Procedure) SpO2 (Oxygen Saturation) = Percentage of Hemoglobin SUSAR Suspected unexpected serious adverse reaction Adverse events that occurred during TEAE treatment TFLs: Tables, Figures, Lists UMSS (University of Michigan Sedation Scale) US United States aspect Phase 1. A method for sedating a pediatric subject, wherein the above method involves 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazole[1,2-a][1,4]benzodiazepine-4-yl]-propionate methyl ester of formula (I). [ka] A method comprising the step of intravenously administering a pharmaceutically acceptable salt thereof to the subject. Phase 2. The initial dose is 100-500 mcg / kg, as described in Phase 1. Phase 3. The method according to Phase 1, further comprising the step of administering to the subject at least one supplemental dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, given after the initial dose or a previous additional dose. Phase 4. The method according to Phase 2, wherein at least one supplemental dose is administered at least two minutes after the initial dose or previous supplemental dose. Phase 5. The method according to Phase 4, wherein at least one supplemental dose is administered at least two minutes after the initial dose. Phase 6. The method according to Phase 1, wherein the pharmaceutically acceptable salt is a besylate. Phase 7. The method described in Phase 1, wherein the pediatric subject is sedated for less than 30 minutes.

Claims

1. A method for sedating a pediatric subject during a procedure, wherein the method comprises 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazole[1,2-a][1,4]benzodiazepine-4-yl]-methyl propionate of formula (I) (remimazolam) 【Transformation 3】 A method comprising the step of intravenously administering the besylate of the subject to the subject.

2. The method according to claim 1, wherein the initial dose of remimazolam besylate is a bolus dose.

3. The method according to claim 1 or claim 2, wherein the initial dose is a bolus dose in the amount of remimazolam free base of about 100 to about 500 mcg / kg.

4. The method according to any one of the above claims, wherein the initial dose is a bolus dose in the amount of approximately 200 mcg / kg of remimazolam free base.

5. The method according to any one of the above claims, wherein the initial bolus dose is administered over approximately one minute.

6. The method according to any one of the preceding claims, further comprising the step of intravenously administering at least one supplemental dose of remimazolam besylate to the subject.

7. The method according to claim 6, wherein the at least one supplemental dose is about 100 to about 200 mcg / kg of remimazolam free base.

8. The method according to claim 6 or 7, wherein the at least one supplemental dose is administered as a bolus dose.

9. The method according to any one of claims 6 to 8, wherein the at least one supplemental dose of remimazolam besylate is administered after the initial dose and before the commencement of the procedure.

10. The method according to claim 9, wherein the at least one supplemental dose is about 200 mcg / kg of remimazolam free base.

11. The method according to any one of claims 6 to 8, wherein the at least one supplemental dose of remimazolam besylate is administered after the initial dose and during the procedure.

12. The method according to any one of claims 6 to 11, wherein the at least one supplemental dose is administered at least three minutes after the initial dose.

13. The method according to any one of claims 6 to 12, wherein one supplemental dose of remimazolam besylate is administered intravenously.

14. The method according to any one of claims 6 to 12, wherein two supplemental doses of remimazolam besylate are administered intravenously.

15. The method according to any one of claims 6 to 12, wherein three supplemental doses of remimazolam besylate are administered intravenously.

16. The method according to any one of claims 6 to 12, wherein four supplemental doses of remimazolam besylate are administered intravenously.

17. The method according to any one of claims 6 to 12, wherein five supplemental doses of remimazolam besylate are administered intravenously.

18. The method according to any one of claims 14 to 17, wherein the second supplemental dose is administered at least 3 minutes after the first supplemental dose.

19. The method according to any one of claims 15 to 18, wherein the third supplemental dose is administered at least three minutes after the second supplemental dose.

20. The method according to any one of claims 1 to 7, wherein the continuous infusion dose of remimazolam besilate is administered intravenously after the initial dose of remimazolam besilate.

21. The method according to claim 20, wherein the continuous infusion dose of remimazolam besylate is remimazolam free base between 0 and 80 mcg / kg / min.

22. The method according to any one of claims 20 to 21, further comprising the step of gradually increasing the injection dose.

23. The method according to claim 22, wherein the injection dose is increased stepwise by 10 mcg / kg / min of remimazolam free base.

24. The method according to any one of claims 22 to 23, wherein the injection dose is gradually increased to 20 mcg / kg / min of remimazolam free base.

25. The method according to any one of claims 22 to 23, wherein the injection dose is gradually increased to 40 mcg / kg / min of remimazolam free base.

26. The method according to any one of claims 22 to 23, wherein the injection dose is gradually increased to 80 mcg / kg / min of remimazolam free base.

27. The method according to any one of claims 22 to 26, wherein the stepwise increase is administered at least three minutes after the initial bolus dose.

28. The method according to any one of claims 20 to 27, further comprising the administration of a bolus dose of remimazolam besylate, which is approximately 200 mcg / kg of remimazolam free base.

29. The method according to claim 26, wherein the bolus dose is administered at least 3 minutes after any previous bolus dose or infusion increase.

30. The method according to any one of the preceding claims, wherein the patient's sedation is a University of Michigan Sedation Scale (UMSS) score of 2 to 3.

31. The method according to any one of the above claims, wherein the sedation of the patient is approximately Nurse Sedation Interpretation Score (NISS) 2.

32. The method according to any one of the above claims, wherein the procedure is carried out for two hours or less.

33. The method according to any one of the preceding claims, wherein the procedure is an endoscopic examination, lumbar puncture, bone marrow aspiration, imaging, dental procedure, painful bandage change, postoperative procedure requiring sedation, cardiac catheterization, or central venous catheter insertion.

34. The method according to any one of the above claims, wherein the procedure is a nerve block, central venous catheter removal, or conscious intubation.

35. The method according to any one of the above-mentioned claims, wherein the procedure is completed.

36. The procedure according to any one of the above claims, wherein the procedure does not require the administration of a rescue sedative.

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