Use of remimazolam for pediatric sedation

Abstract

The application is directed to methods of sedating a pediatric subject by administering intravenously to the subject remimazolam, or a pharmaceutically acceptable salt thereof.

Description

USE OF REMIMAZOLAM FOR PEDIATRIC SEDATIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 519,082, filed August 11, 2023, the entirety of which is incorporated by reference herein.BACKGROUND

[0002] Pediatric procedural sedation is predominantly undertaken for non-painful procedures outside the operating department. It should be performed by specialist staff experienced and trained in the management of cardiorespiratory depression in children.

[0003] Both IV and non-IV routes of administration are used in pediatric procedural sedation, however the IV route is preferred whenever possible, especially where maximal efficiency and throughput is desirable (e.g., urgent imaging for diagnostic purposes). The rapid and predictable onset of action means titration is easier and recovery potentially quicker. In addition, if inadequate sedation or serious adverse events occur, lack of IV access may impede further management.

[0004] Medications used for non-painful procedural sedation in children include dexmedetomidine, etomidate, midazolam, propofol, ketamine, clonidine as well as short acting barbiturates (pentobarbital, methohexital). For longer procedural sedation (e.g., MRI scanning), propofol or dexmedetomidine are the most commonly used sedative agents. Both drugs are effective but have some safety disadvantages. Propofol is associated with more airway intervention or IV fluid administration and dexmedetomidine with marked bradycardia, particularly in infants

[0005] Remimazolam (CNS7056) is a benzodiazepine developed as an ultra-short-acting intravenous (IV) sedative for use in adults undergoing procedural sedation, general anaesthesia and in intensive care units. Sedation is observed starting at single bolus doses of 0.05 to0.075 mg / kg remimazolam in healthy young adults, with an onset of 1 to 2 minutes. Induction of mild to moderate sedation is associated with plasma levels of approximately 0.2 mcg / mL. Loss of consciousness is seen at doses of 0.1 mg / kg (elderly) or 0.2 mg / kg (healthy young adults) and associated with plasma concentrations of approximately 0.65 mcg / mL. Depth, duration andrecovery from sedation are dose-dependent. Time to fully alert is approximately 10 minutes for 0.075 mg / kg of remimazolam.

[0006] Like other benzodiazepines, remimazolam is associated with cardiovascular and respiratory related events such as hypotension, bradycardia, apnoea and hypoxia. Respiratory depression (decrease in the rate of breathing and / or volume of each breath) is usually temporary and resolves by stimulating the patient or by reducing the dose of the sedative drug. Oxygen may be needed to restore haemoglobin oxygen saturations. Cardiovascular depression (decrease in heart rate and / or blood pressure) is common but usually not significant and treatment is not usually required. Depression of vital signs can often be predicted from the remimazolam dose administered, and has been observed less frequently in comparison to midazolam or propofol. Airway obstruction is a common consequence of depression of consciousness (i.e., sedation deeper than conscious or minimal sedation). It occurs when the tongue obstructs the pharynx or when secretions are not swallowed and pool in the pharynx. If these are untreated, hypoxia will occur within 20-30 seconds and in even less time in small children and infants. Minor airway interventions are usually needed such as jaw thrust, inserting oropharyngeal airway or removing secretions. Risks associated with sedation of children may be higher because children have smaller airways and have enlarged tonsils and adenoids making rescue airway maneuvers more difficult than in adults. Autonomic activity may also be higher, thus increasing the risk of arrhythmias and vasovagal response in comparison with adults.

[0007] While remimazolam has been approved by the United States Food and Drug Administration for induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less, it has not yet been established as safe and effective for sedation in patients less than 18 years old. Though much is known about remimazolam’ s use in adults, that information is not generally translatable to sedation in pediatric patients for many reasons. Sedation of pediatric patients for procedures differs from adult sedation in several ways. For example, while an adult may require only mild to moderate sedation for a procedure to be completed, pediatric subjects typically must be more deeply sedated in order for a procedure to be successfully completed. In addition, it can often be the case that a procedure that can be performed in 30 minutes or less on an adult will require longer than 30 minutes when the same procedure is performed on a child. Moreover, an adult’s level of sedation with remimazolam has been validated using the 6-point Modified Observer’s Alertness / Sedation Scale (MOAA / S). Incontrast, the 5-point University of Michigan Sedation Scale (UMSS) is considered more relevant for monitoring pediatric sedation, confounding the ability to apply adult sedation data to pediatric patients.

[0008] Remimazolam’s pediatric pharmacodynamics is unclear. For example, clearance of remimazolam in neonates might be slower than in adults because CES1 is less abundant in neonates than in adults and as a consequence its enzymatic activity is lower. While a change in clearance will not enhance the sedative effect of remimazolam (i.e., not result in a deeper level of sedation), reduced clearance may prolong the effect, resulting in potential 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 following treatment with benzodiazepines in children. While Agitation and Delirium TEAEs have not been observed in clinical trials with remimazolam for procedural sedation in adults, in clinical trials in for deeper sedation, for example, general anaesthesia, the incidence of Agitation and Delirium TEAEs was 11.1% for remimazolam.

[0010] Methods of safely and effectively using remimazolam for sedation in a pediatric population are needed.BRIEF SUMMARY

[0011] The disclosure is directed to methods of sedating a pediatric subject during a procedure comprising administering intravenously to the subject 3-[(4S)-8-bromo-l-methyl-6-(2- pyridinyl)-4H-imidazol[l,2-a][l,4]benzodiazepine-4-yl] -propionic methyl ester of formula (I) (Remimazolam) besylate.CD

[0012] These and other objects and advantages shall be made apparent from the accompanying drawings and the description thereof.BRIEF DESCRIPTION OF THE FIGURES

[0013] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments, and together with the general description given above, and the detailed description of the embodiments given below, serve to explain the principles of the present disclosure.

[0014] Figure l is a graph showing computer modeling of a steady-state pharmacodynamic interaction between fentanyl and remimazolam. See Example 2. The predicted probability for UMSS = k with k 6 {0, 1, 2, 3} for different combinations remimazolam - fentanyl according to the pharmacodynamic model. The calculated remimazolam effect-site concentration driving the pharmacodynamic effect is depicted on the x-axis. The background fentanyl regimens, expressed as predicted effect-site concentrations, are depicted by different linetypes: no fentanyl coadministration (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 predicted remimazolam effect-site concentrations from this study are denoted by the shaded area.

[0015] Figure 2 is a flow chart describing administration for both bolus and infusion dosing regimens targeting different sedation level and opioid requirement. All dose calculations should be rounded to 2 decimal places for patients weighing <25 kg and to 1 decimal place for patients weighing >25 kg. For this trial, opioids should not be administered from 60 to 5 minutes prior to the start of remimazolam. For this trial, opioid boluses can be administered during the procedure; top-up remimazolam boluses should not be given within 2 minutes after an opioid dose. Opioid boluses should not be administered within 2 minutes of a remimazolam bolus.

[0016] Figure 3 is a diagram describing administration and timing of PK samples in relation to safety and PD assessments during the bolus regimen. * After procedure start; ** Not needed if 2nd or 4th remimazolam top-up not administered during procedure; *** Post-procedure labs required at the same time as the last PK sample. If no PK sampling is intended or performed after the end of the procedure the post-procedure lab test can be performed any time after the procedure, prior to being fit for discharge. Vital signs (body temperature, mean non-invasive blood pressure, heart rate, respiratory rate, SpO2) remimazolam top-up boluses each at least 3minutes apart (from the start time of one bolus to the next) 8th PK sample can be for cohort 1 children >6 to <18 years.

[0017] Figure 4 is a diagram describing administration and timing of PK samples in relation to safety and PD assessments during the infusion regimen. ** Not needed if procedure lasts less than 15 minutes. The 4th scheduled PK sample is taken at 30 minutes unless end of procedure is envisaged within 5 minutes, where this PK sampling timepoint can be omitted. ***Post- procedure labs required at the same time as the last PK sample. If no PK sampling is intended or performed after the end of the procedure the post -procedure lab test can be performed any time after the procedure prior to being fit for discharge. Vital signs (body temperature, mean non- invasive blood pressure, heart rate, respiratory rate, SpO2). Remimazolam top-up boluses each at least 3 minutes apart (from the start time of one bolus to the next). 8th PK sample can be for cohort 1 children >6 to <18 years.DETAILED DESCRIPTION

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

[0019] When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0020] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separateembodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0021] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude an optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step 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 child, i.e., younger than 18 years of age.

[0023] “Treating” or variations thereof refers 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 a discernible symptom), physiologically, (e.g, stabilizing a physical parameter), or both. In further embodiments, “treating” refers to delaying onset of the disease or disorder.

[0024] The disclosure is directed to methods of safely and effectively sedating pediatric patients with remimazolam, or a pharmaceutically acceptable salt thereof, for example remimazolam besylate. As used herein, a pediatric patient will be considered sedated within the scope of the disclosure when the patient’s sedation is determined to be a University of Michigan Sedation Scale (UMSS) score of about 2 to about 3, for example, 2 to 3. In some aspects, the patient will be considered sedated within the scope of the disclosure when the patient’s sedation is a UMSS score of 2. In some aspects, the patient will be considered sedated within the scope of the disclosure when the patient’s sedation is a UMSS score of 3. In other aspects, patient will be considered sedated within the scope of the disclosure when the patient’s sedation is determined to be a Nurse Interpretation of Sedation Score (NISS) of about 2, for example 2.

[0025] Pediatric patients can be sedated using the methods of the disclosure for procedures lasting about 2 hours or less. In some aspects, the procedure lasts about 2.5, 2, 1.5, or 1 hour. In other aspects, the procedure lasts less thn one hour, for example 45 minutes, 30 minutes, or 15 minutes. These procedures can include, for example, an endoscopy, a lumbar puncture, bone marrow aspiration, imaging (for example, X-ray, MRI, computed tomography (CT), interventional radiography), a dental procedure, a changing of a painful dressing, a post-surgical procedure requiring sedation, cardiac catheterization, or central venous catheter insertion. Other suitable procedures include a nerve block, a central venous catheter removal, and awake intubation. Procedures performed using the sedation methods described herein will be successfully completed without the need for the administration of any rescue sedative medication.

[0026] According to the described methods, 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 aspects, the initial dose is a bolus dose. The initial bolus dose is in an amount of from about 100 micrograms / kg (mcg / kg) to about 500 mcg / kg. Dosage amounts described herein are by reference to remimazolam free base. The moleculr weight of remimazolm free base is 439.3 g / mol. The molecular weight of remimazolam besylate is 597.5 g / mol. Those of ordinary skill in the art administering remimazolam besylate will be able to readily calculate the equivalent dose of remimazolam free base.

[0027] In some aspects, the pediatric subject is administered an initial bolus dose of remimazolam besylate in an amount of 100 mcg / kg of remimazolam free base. In other aspects, the pediatric subject is administered an initial bolus dose of remimazolam besylate in an amount 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 preferred aspects, the pediatric subject is administered an initial bolus dose of remimazolam besylate in an amount of 200 mcg / kg of remimazolam free base.

[0028] The initial bolus dose is to be administered over period of time that is 5 minutes or less, for example about 5, 4, 3, 2, or 1 minute. In some aspects, the initial bolus dose is administered over a period of time that is less than one minute or less than 30 seconds. Preferably, the initial bolus dose is to be administered over period of time that is about 1-2 minutes, for example 1-2minutes. More preferably, the initial bolus dose is to be administered over period of time that is about 1 minute, for example, 1 minute.

[0029] After the pediatric subject is administered 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 will be administered at least about 3 minutes after the initial bolus dose.

[0030] The at least one or more supplemental doses can be administered as bolus, continuous, or a combination of bolus and continuous. According to the disclosure, each of the one or more supplemental doses are administered after the initial bolus dose. In some aspects, one or more supplemental doses are administered before the start of the procedure. In some aspects, one or more supplemental doses are administered during the procedure. In some aspects, at least one supplemental dose is administered before the start of the procedure. In other aspects, no supplemental doses are administered before the start of the procedure. In some aspects at least one supplemental dose is administered during the procedure. In other aspects, no supplemental doses are administered after the start of the procedure. In some aspects, one or more supplemental doses are administered before the start of the procedure and one or more doses are administered during the procedure.

[0031] Preferably, the one or more supplemental doses are of remimazolam besylate. In some aspects, the pediatric subject is administered 1 supplemental dose of remimazolam besylate. In some aspects, the pediatric subject is administered 2 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 3 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 4 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 5 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 6 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 7 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 8 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 9 supplemental doses of remimazolam besylate. In some aspects, the pediatric subject is administered 10 supplemental doses of remimazolam besylate. Preferably, the pediatric subject is administered between 1 and 5 supplemental doses ofremimazolam besylate. In some aspects, the pediatric subject is not administered any supplemental doses of remimazolam besylate.

[0032] According to the disclosure, the administration of any supplemental dose will be preceded by a gap at least about 1 minute from any prior supplemental dose. In some aspects, the administration of any supplemental dose will be preceded by a gap at least about 1, 1.5, 2, 2.5, 3, or 3.5 minutes from any prior supplemental dose. In preferred aspects, administration of any supplemental dose will be preceded by a gap at least about 3 minutes, for example 3 minutes, from any prior supplemental dose. By way of example, if two supplemental doses are administered, the second supplemental dose is administered at least 3 minutes after the first supplemental dose. Also by way of example, if three supplemental doses are administered, the third supplemental dose is administered at least 3 minutes after the second supplemental dose. Also by way of example, if four supplemental doses are administered, the fourth supplemental dose is administered at least 3 minutes after the third supplemental dose. Also by way of 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 the disclosure, any one or more of the supplemental doses can be administered as a bolus dose. In those aspects, the supplemental dose of remimazolam besylate is about 100 mcg / kg to about 300 mcg / kg of remimazolam free base. In some aspects, the supplemental bolus dose of remimazolam besylate is 100, 200, or 300 mcg / kg of remimazolam free base. In some aspects, the 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 preferred aspects, supplemental bolus dose of remimazolam besylate is about 200 mcg / kg, for example, 200 mcg / kg of remimazolam free base.

[0034] In other aspects of the disclosure, any one or more of the supplemental doses can be administered as a continuous intravenous dose, after the initial bolus dose. Any one or more of the supplemental doses that is administered as a continuous intravenous dose will be administered at least about 3 minutes after the initial bolus dose. According to the disclosure, any one of the supplemental bolus doses can be administered over a time period that is 5 minutes or less, for example 5, 4, 3, 2, or 1 minute. In some aspects, a supplemental bolus dose can be administered over a time period that is about 1-2 minutes, for example 1-2 minutes. In someaspects, a supplemental bolus dose can be administered over a time period that is less than one minute or less than 30 seconds.

[0035] In those aspects where a supplemental dose is administered as a continuous intravenous dose, the infusion rate will be between about 0 mcg / kg / min to about 80 mcg / kg / min of remimazolam free base during the remainder of the procedure. For example, where a supplemental dose is administered as a continuous intravenous dose, the infusion rate can be about 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, 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 aspects where a supplemental dose is administered as a continuous intravenous dose, the infusion dose can be increased. In these aspects, the infusion dose is increased stepwise. In some aspects, the infusion dose is increased stepwise by 10 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 15 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 20 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 25 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 30 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 35 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 40 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 45 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 50 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 55 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 60 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 65 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 70 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 75 mcg / kg / min of remimazolam free base. In some aspects, the infusion dose is increased stepwise by 80 mcg / kg / min of remimazolam free base. According to the disclosure, any stepwise increase will be preceded by a gap of at least about 1 minute, for example, about 1,1.5, 2, 2.5, 3, or 3.5 minutes. In some aspects, any stepwise increase will be preceded by a gap of at least about 3 minutes, for example, 3 minutes.EXAMPLE 1

[0037] Primary objective: To assess the efficacy of IV remimazolam in inducing and maintaining suitable sedation levels for pediatric patients undergoing diagnostic and / or therapeutic procedures.

[0038] Primary endpoint: Success of the procedure, defined as all of the following:Completion of the procedure ANDNo requirement for a rescue sedative medication ANDNo requirement for more than the permitted remimazolam bolus / infusion regimen

[0039] Successful conduct of the procedure without any rescue sedative medication implies that the sedative effects of remimazolam are satisfactory. A similar primary endpoint was used in Phase 3 clinical trials in adults and was accepted by FDA and EMA as appropriate for the approval of remimazolam for procedural sedation in adult.

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

[0041] Secondary efficacy endpoints:- Target depth of sedation achieved (Target depth of sedation on the UMSS will be predefined per patient based on the procedure and patient needs before the procedure.)- Target range of sedation (i.e., UMSS 2-3) achieved during 80% of procedure duration- Percentage of time within target range of sedation during the procedure- Adequacy of sedation, assessed as NISS over time- Time to target sedation level and start of procedure after first dose of remimazolam [minutes]- Time to fully alert (defined as the first of three consecutive UMSS scores of 0) after end of procedure and end of last dose of remimazolam [minutes]- Signs of re-sedation i.e., after reaching a UMSS of 0 after end of procedure, whether a UMSS score of >0 was seen in the time until discharge.- Time to fit for discharge after end of procedure and end of last dose of remimazolam[minutes]- Success of the procedure, excluding cases where the procedure could not be completed for non-sedative reasons. Defined as all of the following:- Completion of the procedure AND- No requirement for a rescue sedative medication AND- No requirement for more than the permitted remimazolam bolus or infusion regimen

[0042] Secondary safety endpoints:Treatment-emergent adverse events (TEAEs) after initiation of remimazolamVital signs (heart rate, mean non-invasive blood pressure, body temperature, respiratory rate and SpCh)Need for any manual or mechanical ventilation, including mask ventilation without insertion of LMA / IGEL / ETTNeed for the reversal agent flumazenil, including reasons / indication for use Emergence Delirium (pediatric anaesthesia emergence delirium scale) after end of procedure until fit for discharge.PK assessments:

[0043] After initiation of remimazolam, PK sampling will be performed for PK data analyses. The PK data will be displayed graphically against the predicted PK from the PK / PD model for each of the age groups. Adequacy of the predicted doses will be assumed if the individually obtained values fall between the confidence limits of the predictions (venous concentration at 1 minute and 5 minutes after initial dosing).

[0044] Since the Modified Observer's Alertness / Sedation (MOAA / S) scale, which was used in adult Phase 3 remimazolam trials is not reliable in children, the UMSS and the NISS have been selected for this trial. The UMSS has been reported to be a simple, valid and reliable tool that facilitates rapid and frequent assessment and documentation of depth of sedation in children. It was also used in the dexmedetomidine pivotal PICU trial which has been assessed by EMA. In addition, the NISS will be used for secondary endpoints as advised by the PDCO. Taking into consideration the diverse patient characteristics and patient needs as well as the different duration and invasiveness of procedures in this trial, the maximum depth of sedation will be predefined for each patient individually. At least 80% of procedure duration spent in the target range of sedation is considered sufficient to reflect remimazolam’ s sedation maintenance effects.

[0045] The onset and recovery profile of remimazolam will be assessed using time-to-event endpoints. The onset and recovery profile reflects the potency of remimazolam as an ultra shortacting sedative.

[0046] A need for the reversal agent flumazenil indicates over-dosing of remimazolam and will be assessed as a secondary safety endpoint.

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

[0048] Pediatric Emergence Delirium is a phenomenon whose implications and risks factors are not fully understood. Emergence agitation is reported in up to 18% of children 3 to 7 years old. Another study reported ‘post-anaesthetic excitement’ in 13% of children aged 3 to 9 years and 9% in those 10-19 years. Other factors such as volatile anaesthetics, type of surgery, parental / patient anxiety, patient pre-existing behaviour and patient and parent interaction with healthcare providers can contribute to pediatric emergence delirium. Therefore, emergence delirium will be monitored during the recovery period in this trial.

[0049] Since this trial is the first one within the overall pediatric development program it will guide doses to be used in all age groups for different indications. This is also the trial with the least vulnerable patients (overall relatively healthy as compared to patients in the planned general anaesthesia and the ICU sedation trials) as well as with a short exposure and relatively low dose. Initial doses / dosing regimens for this trial are predicted based on target concentrations from adult trials. It is therefore essential to assess the accuracy of these predictions by PK sampling and, if necessary, to adapt the dosing for the next lower age group. PK results of this trial will also inform whether pharmacodynamics of remimazolam is different in children, i.e., whether children of a given age group show the same degree of sedation as adults at a given plasma concentration.

[0050] Given the small number of patients per age group as well as the expected variability of different procedures and flexible dosing a sparse sampling or a population PK approach is not possible. A sample size calculation based on the normal variability in the PK model yielded a minimum sample size of 20 patients aged >6 to <18 years (cohort 1), 20 patients aged >3 to <6 years (cohort 2). As a consequence, if the minimum requirement of PK samples per cohort has been achieved, PK sampling for the remaining patients in that cohort may not be mandatory.

[0051] 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 trial duration for any patient will be 28 days; patients will be screened within 21 days prior to the procedure, and a follow-up contact will be performed on Day 4 (+3 / -1 days) following the procedure.

[0054] For each patient, one of the two different dosing regimens can be chosen, depending on the procedure and patient needs:Dosing with an initial bolus followed by one or multiple top-up boluses when requiredDosing with an initial bolus followed by continuous infusion that can be adjusted to the required depth of sedation

[0055] Approximately half of the patients enrolled on the study will receive an initial bolus and top-up regimen and half of the patients will receive an initial bolus followed by a continuous infusion regimen.

[0056] The trial will start with a subset of patients from cohort 1 (>12 to <18 years) for at least the first 5 patients and then progresses to the remaining patients in cohort 1, before proceeding to the lower age group (cohort 2).

[0057] In total, at least 100 patients will be recruited:Cohort 1 : >6 to <18 years (at least 40 patients; of which minimum n = 30 aged >6 to <12 years)Cohort 2: >3 to <6 years (n = 35)

[0058] The dose for the age groups >6 to <18 years and >3 to <6 years targeting moderate to deep sedation (UMSS scores 2-3) with opioid premedication was simulated using a PK / PK model for remimazolam using an adult reference of remimazolam 5 mg targeting moderate sedation with opioid premedication.

[0059] Development of Trial DesignDosing Regimen One

[0060] The dose for the age groups >6 to <18 years and >3 to <6 years targeting moderate to deep sedation (UMSS scores 2-3) with opioid premedication was simulated using a PK / PD model for remimazolam using an adult reference of remimazolam 5 mg targeting moderatesedation with opioid premedication. In adults, the initial dose of remimazolam targeting moderate sedation without opioid is 7 mg; therefore, the initial dose for moderate to deep sedation (UMSS scores 2-3) without opioid was up-scaled, accordingly. The initial dose for mild to moderate sedation (UMSS scores 1-2) with or without opioid is 50% of the dose for moderate to deep sedation (UMSS scores 2-3) with or without opioid; respectively. Top-ups were, in line with prior dosing regimens, set at 50% of the initial bolus.

[0061] Alternatively, a dosing regimen comprising an initial bolus followed by a continuous infusion can be used for long and invasive procedures based on the patient’s needs. The reference dose for adults, initial dose of 5 mg with opioid premedication to achieve moderate sedation, was used to simulate the infusion rate of 3.5 mcg / kg / min to achieve moderate to deep sedation (UMSS scores 2-3) with concomitant opioid administration, to maintain target plasma concentration of 200 ng / mL, ranging 100-300 ng / mL.

[0062] The infusion dosing may be more convenient than bolus administration. Pediatric anaesthetists might prefer this dosing method for certain procedures e.g., imaging.

[0063] Dosing Regimen Two

[0064] As part of the pediatric study plan agreed with the US FDA, a clinical trial was initiated in 2021 to assess the efficacy and safety of IV remimazolam in inducing and maintaining sedation in pediatric patients undergoing diagnostic and / or therapeutic procedures. See Example 2. An interim analysis of the pharmacokinetics and pharmacodynamics of remimazolam was used to conduct a model -based optimization of the dosing regimen. 31 patients (6 to 18 years old) were included in that trial and were stratified across 4 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. After dosing of the first 5 patients, 3 of whom had received the infusion regimen and 2 the bolus and top-up regimen, a review of the patient data was performed. Three patients required rescue sedative medication to be able to complete the procedure; therefore, the dosing regimen was reconsidered. The data suggested that the level of sedation seen in the pediatric patients was consistent with that seen in adults for a given dose i.e., a moderate sedation corresponding to MOAA / S levels 2-3 in adults and UMSS 2 in children. However, it was apparent that investigators were requiring a somewhat deeper level of sedation for children (i.e., UMSS 3), to minimise movement during the procedure. Therefore, to facilitate this deeper sedation, the initialbolus and starting infusion dose have both been increased for procedures with a target UMSS score of 2-3. In addition, the maximum permitted infusion dose has been harmonised across the different dosing regimens at a level consistent with that shown to be safe in adults. In the patients who required rescue sedative medication, target sedation was never achieved, suggesting that the 50% top-up doses were not able to increase plasma concentrations above those achieved by the initial bolus. Therefore, flexibility was introduced into the trial design to allow the top-up bolus to be 50-100% of the initial bolus to enable the level of sedation to be deepened if it is inadequate for the clinician’s needs after the initial bolus.

[0065] Dosing Regimen Three

[0066] A review of efficacy and PK data was conducted after 31 pediatric subjects (see Example 2, infra) had completed cohort 1. Suboptimal efficacy of the Dosing Regimen Two was still noted. A PK / PD analysis revealed that the PK was as predicted i.e., the initial doses of the dosing regimen resulted in the targeted plasma concentration range. However, even after exceeding the targeted plasma concentration range by additional bolus doses or increasing the infusion rate to the upper allowed range a UMSS of 3 could not be reliably reached. This was particularly the case for children weighing 47 kg or more i.e., for whom the bolus and infusion dose was capped. Therefore, the dosing regimen was once more amended based on a PK / PD model designed from the data of the first 31 children enrolled.

[0067] Based on this information gathered and analyzed from Dosing Regimens One, Two, and Three, the present trial design was developed by incorporating the following changes:The dosing regimen focuses on moderate to deep sedation only i.e. UMSS levels of 2-3, The vast majority of patients recruited so far needed a UMSS of 2 or 3. Therefore light sedation was excluded and dosing focuses solely on moderate to deep sedation.For the initial and top-up boluses the previous dosing cap, which has been implemented as part of the adult dosing regimen, has been removed since particularly children for whom the dose was capped needed rescue sedation.The strength of the initial bolus has been increased from 150 mcg / kg to 200 mcg / kg because the vast majority of patients needed multiple bolus doses before reaching the target UMSS score.For the same reason, the strength of the top-up bolus was set at the same strength as the initial bolus i.e., to reduce the number of dosings and time prior to start of procedure. In line withthis, the duration of top-up bolus administration has been increased to 1 minute (i.e., to have the same duration of administration for the same dose). For the maintenance of adequate sedation, a top-up bolus of half of the initial strength is still possible.The initial infusion rate and the permitted range was increased since multiple additional boluses were needed during infusion to reach / maintain the targeted sedation level. While a bolus dose was introduced before each increase of infusion rate, no boluses are allowed during infusion at a constant rate.Specific dosing instructions for patients receiving fentanyl were removed since fentanyl is used at low doses and hence the level of synergism for sedation is less than anticipated. Furthermore, fentanyl is purely used to provide analgesia during painful procedures.

[0068] The dosing regimen is shown in Table 4.Table 4 Remimazolam doses for bolus and infusion regimens: cohort 1 and cohort 2

[0069] TRIAL POPULATION

[0070] Inclusion Criteria

[0071] A pediatric patient can be included into the trial if he / she meets all of the following inclusion criteria:1. Signed informed consent and assent (if applicable) form and willingness of patient and parent(s) to participate in the trial.2. In US sites: Pediatric male or female patient, aged >3 and <18 years scheduled to undergo a diagnostic or therapeutic procedure, which is medically indicated and independent from the trial.3. Maximum planned duration of procedure: 2 hours4. ASA Physical Status I-III5. Planned spontaneous breathing during sedation6. A female who is of child-bearing potential (i.e., after menarche) and sexually active must use a highly effective method of birth control during the trial period (from the time of consent until all study procedures are completed). These include:Intrauterine system or devicesHormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections).7. For females of child-bearing potential (i.e., after menarche), a negative pregnancy test at screening and on treatment day. Only needs to be performed once if screening is on the same day as the treatment day.8. A procedure targeting UMSS 2-3 sedation levelExclusion Criteria

[0072] A pediatric patient who meets any of the following criteria will be excluded from participation in this trial:1. Emergency procedures2. Condition / procedure that requires planned airway control via endotracheal tube or LMA insertion3. Cranio-facial malformation, which would severely limit the possibilities for emergency airway rescue4. Other abnormalities relating to the airway (including large tonsils and anatomical abnormalities of upper airway or lower airway) which may compromise emergency airway rescue5. Known hypersensitivity to benzodiazepines, flumazenil, dextran or any of the ingredients of the remimazolam drug product6. Known paradoxical reactions to benzodiazepines7. History of sleep apnoea8. Active respiratory failure9. Active neuromuscular disease10. Active cardiac failure11. Active hepatic failure12. Pregnant or Breast-feeding females13. Prohibited medication:• Any investigational drug other than remimazolam when taken within 30 days or less than 7 half-lives (whichever is longer) before Treatment Day.• Any medicine other than remimazolam administered for sedative purposes (apart from use of nitrous oxide to facilitate IV cannula placement, which is permitted)• Clonidine• Ringers lactate or Acetate solution administered together with remimazolam using the same intravenous line14. Any patient judged to be inappropriate for the trial for any other reason15. Body mass index (BMI)for age percentile equal or greater than the 95thpercentile

[0073] Recruitment

[0074] Patients with medically indicated procedures (<2 hours) requiring sedation with or without local / IV analgesia can be enrolled. It is expected that these procedures differ between age groups. Likely ones are listed as examples below per age group:

[0075] >6 to <18 years:EndoscopiesLumbar puncturesBone marrow aspirationImagingDental proceduresChanging of painful dressings and other post-surgical procedures requiring sedation Cardiac catheterizationCentral venous catheter insertion

[0076] >3 to <6 years:EndoscopiesLumbar puncturesImagingDental proceduresChanging of painful dressings and other post-surgical procedures requiring sedationCardiac catheterizationCentral venous catheter insertion

[0077] TRIAL MEDICATIONS

[0078] Dosing and administration

[0079] Two different dosing regimens can be chosen:Dosing with an initial remimazolam bolus followed by top-up boluses when required Dosing with an initial remimazolam bolus followed by continuous infusion that can be adjusted to the required depth of sedation

[0080] The dosing regimen to be used will be determined for each patient before the start of dosing. It is likely that a continuous infusion will be used for procedures lasting over 30 minutes. In addition, the choice of dosing regimen can be made based on the preference and the accessibility of the patient (e.g. top-up dosing may be difficult during an MRI scan).

[0081] If the procedure is expected to be painful, local anaesthesia and / or an analgesic is allowed according to local standards.

[0082] Dosing and administration for age group >6 to <18 years (cohort 1)

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

[0084] Figure 2 presents a flow chart describing administration for both bolus and infusion dosing regimens targeting different sedation level and opioid requirement.

[0085] Figure 3 presents a diagram describing administration and timing of PK samples in relation to safety and PD assessments during the bolus regimen.

[0086] Figure 4 presents a diagram describing administration and timing of PK samples in relation to safety and PD assessments during the infusion regimen.

[0087] dosing with initial bolus and top-ups:

[0088] Bolus doses (200 mcg / kg) will be administered manually by IV injection over approximately 1 minute. If there is insufficient sedation to start the procedure after the initial dosing, one or more top-up doses (200 mcg / kg) may be administered as boluses, at least 3 minutes apart (from the start time of one bolus to the next). When the procedure has been started, adequate sedation can be maintained by additional top-up boluses of 100-200 mcg / kg if required. Considering the synergy with opioids, the frequency of top-up doses is to be adjusted to an appropriate depth of sedation while maintaining the three minute gap between the top-updoses. In respect of the minimum 3 -minute gap, the frequency of top-ups is to be adjusted to the desired depth of sedation taking into account the synergy with opioids. If the desired level of sedation cannot be reached or maintained during any 15 minutes window it is suggested that the remimazolam drug product be discontinued and an alternative rescue sedative agent used. The rescue sedative agent used is at discretion. If significant hemodynamic instability and / or respiratory compromise occur based on clinical judgment, even in the absence of oversedation, measures should be immediately undertaken to treat these conditions, such as using intravenous fluids, use of vasopressors, and / or use of anticholinergic medications. Additionally, the bolus and top-up dose and / or dosing frequency can be reduced.

[0089] Dosing with initial bolus and infusion:

[0090] The initial bolus of remimazolam (200 mcg / kg) will be administered manually by IV injection over approximately 1 minute. This will be followed by a continuous infusion of (10 mcg / kg / min), starting after the end of the initial bolus. If signs of awakening or insufficient sedation are observed a bolus will be administered followed by an increase of the infusion rate to 20 mcg / kg / min. Further increases, first to 40 mcg / kg / min and finally to 80 mcg / kg / min are possible if required. Each increase in infusion rate will be preceded by a remimazolam bolus (200 mcg / kg). There must be at least 3 minutes gap from the start time of one bolus to the next. Dose levels are to be adjusted to the desired depth of sedation, taking into account a synergism with opioids. If the desired level of sedation cannot be achieved or maintained during any 15 minutes window it is suggested that the remimazolam is discontinued and an alternative rescue sedative agent used. The rescue sedative agent used is at discretion.

[0091] If the sedation becomes too deep the infusion can be temporarily stopped. After the procedure has been started the infusion dose can be modified between 0-80 mcg / kg / min at discretion to maintain the ideal level of sedation. Between each increase in infusion rate a 3 minute gap should be kept. If during the procedure the sedation drops to below UMSS of 2, a bolus (200 mcg / kg) is to be administered prior to increasing the infusion rate.

[0092] If significant hemodynamic instability and / or respiratory compromise occur based on clinical judgment, even in the absence of oversedation, measures should be immediately undertaken to treat these conditions, such as through the bolus of intravenous fluids, use of vasopressors, and / or use of anticholinergic medications. Additionally, the infusion can be reduced or stopped, or the frequency or dose of top-up boluses can be reduced.

[0093] Dosing and administration for age groups >3 to <6 years (cohort 2)

[0094] The dosing regimens for age group >6 to <18 years can be used for the younger age group of >3 to <6 years. This is because the PK modelling was simulated for the age range >3 to <18 years, and the remimazolam doses described for >6 to <18 years are also suitable to maintain the target plasma concentrations in children aged >3 to <6 years. All dose calculations should be rounded to 2 decimal places for patients weighing <25 kg; and to 1 decimal place for patients weighing >25 kg.

[0095] Opioid Dosing

[0096] Some procedures, such as endoscopies, lumbar punctures, bone marrow aspiration, some dental procedures, and changing of painful dressings, may require opioid analgesia including fentanyl. Additionally, opioid analgesia may be required for positioning during imaging.

[0097] Opioid analgesia is expected to be synergistic with remimazolam. Opioids must not be administered from 60 to 5 minutes prior to the start of remimazolam dosing (T = 0). Opioid boluses can be administered during the procedure, however top-up remimazolam boluses should not be given within 2 minutes after an opioid dose. Conversely, opioid boluses should not be administered within 2 minutes of a remimazolam bolus.

[0098] Fentanyl Dosing:

[0099] Fentanyl remains one of the most widely used opioids in children undergoing sedation and a vast amount of clinical experience exists relating to its use. The pharmacokinetics of concomitant administration of remimazolam with fentanyl from adult procedural sedation studies, along with clinical experience were used when determining the range of fentanyl doses to be used within the study.Table 5 Fentanyl dosing

[0100] Fentanyl boluses may be administered every 5 minutes as needed, however fentanyl top- up boluses should not be given within 2 minutes after a remimazolam bolus. In addition, remimazolam boluses should not be given within 2 minutes of a fentanyl bolus. A patient will be considered to have exceeded the maximum dose of fentanyl if more than 3 mcg / kg / hr isadministered. If unable to achieve adequate analgesia with doses highlighted above, consider use of alternative analgesia or consider abandoning the case due to inadequate analgesia.

[0101] Local anaesthesia / IV analgesia

[0102] If the procedure is expected to be painful, local anaesthesia and / or an analgesic is allowed according to local standards.

[0103] Nitrous oxide for IV cannula placement

[0104] To facilitate IV cannula placement, nitrous oxide may be administered in accordance with local practice. A minimum of 10 minutes must elapse between cessation of N2O administration and initiation of remimazolam administration. Alternatively, EtN2O must be less than 5% before the initiation of remimazolam administration. Confirm and document in the medical records that the patient has returned to baseline level of sedation prior to initiating remimazolam administration.

[0105] Rescue Sedative Medication(s)

[0106] Rescue sedative medication is defined as any medication given, other than remimazolam, in order to either induce or maintain a suitable sedation level to start or continue with the procedure. Rescue sedative medication would thus be given if adequate sedation by remimazolam could not be induced or maintained. Rescue sedative medication should be administered if the maximum administration of remimazolam specific to the patient’s age group and dosing regimen failed to induce or maintain adequate sedation for the procedure. The procedure can then continue with any other sedative appropriate for pediatric use at discretion (e.g., midazolam, propofol, dexmedetomidine) or rearranged for another occasion.

[0107] Concomitant Medications

[0108] With the exception of the prohibited medications, all other concomitant medication can be administered during the procedure. However, compatibility studies with the majority of concomitant medications and remimazolam are not available; therefore they should not be coinfused with remimazolam.

[0109] During the remimazolam infusion regimen concomitant medication, with the exception of some of the maintenance fluids, must be administered through the PK cannula.

[0110] During the remimazolam bolus and top-up regimen concomitant medication can be administered through the PK cannula or the same cannula as remimazolam administration, provided that the two medicines are not co-administered.[oni] Prohibited Medications

[0112] The following medication will be prohibited after confirmation of eligibility until the patient is considered fit for discharge.Any medicine other than the remimazolam administered for sedative purposes (apart from use of nitrous oxide to facilitate IV cannula placement, which is permitted)ClonidineRingers Lactate or Acetate solution administered together with remimazolam using the same intravenous lineInvestigational drugs other than remimazolamOpioid medication from 60 to 5 minutes before the start of remimazolam

[0113] Inadequate sedation / analgesia

[0114] It is anticipated that situations may be encountered whereby the patient is unable to be sedated to a level which is considered adequate for the procedure being performed. Therefore, the procedure may need to be abandoned. Similarly, procedures may have to be abandoned if there is insufficient analgesia, even if they may have received appropriate sedation.

[0115] Signs of inadequate sedation may beAlert and vocally responsive patientPersistently low UMSS or NISS score

[0116] Signs of inadequate analgesia may bePatient discomfort or patient injury because of lack of cooperation or adverse physiologic or psychological response to stressHypertensionTachycardia

[0117] In the event that the procedure needs to be abandoned all post procedure and follow up procedures should be conducted as per protocol.

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

[0119] Remimazolam beslyate drug product is presented as a sterile, preservative free, white-to- off-white lyophilized powder in a 12 mL vial. Composition of contents in each vial is presented in the Table below. Store between 15 °C and 25 °C, protected from light.Table 6 Composition in a 12 mL vial

[0120] Preparation

[0121] Remimazolam drug product needs to be reconstituted with sterile 0.9% NaCl solution to yield a concentration of 1.0 mg / mL solution for injection.

[0122] TRIAL ASSESSMENTS AND PROCEDURES

[0123] Efficacy assessmentsLevel of sedation will be assessed over time using the University of Michigan Sedation Scale (UMSS; Table 7). Timings of assessments are defined herein.Table 7 University of Michigan Sedation Scale

[0124] Adequacy of sedation will be assessed over time using the Nurse Interpretation of Sedation Score (NISS; Table 8). Timings of assessments are defined in herein.Table 8 Nurse Interpretation of Sedation Score

[0125] PK sampling

[0126] Venous plasma samples will be taken as outlined herein. Volumes per sample are 300 pL of blood and a maximum of 7 samples (n=8 for the age group >6 to <18 years) will be taken for PK analysis. The total volume of blood sampled during the trial for the purposes of PK will be 2.1 mL (2.4 mL for the age group >6 to <18 years).

[0127] PK samples during the MRI procedure are preferable but not mandatory.

[0128] Safety assessmentsPhysical examination: including at least cardiovascular, respiratory and any other body systems where a pathology is suspected.Urine pregnancy test (HCG) as dip stick for all female participants who are of childbearing potential (i.e. after first menarche).Mean non-invasive blood pressure will be measured. For a given patient the measurement device will remain at the same position on the treatment day.

[0129] ASA physical status classification (Table 9)Table 9 ASA physical status classification

[0130] Post-sedation agitation will be assessed using the pediatric anaesthesia emergence delirium (PAED) scale (Table 10) from the end of procedure until fit for discharge from recovery room.Table 10 Pediatric anaesthesia emergence delirium scale

[0131] Adverse Events and Serious Adverse Events

[0132] Definition of Adverse Events (AE)

[0133] An AE is defined as any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including clinically significant abnormal values from relevant tests, such as clinical safety laboratory tests, ECGs, vital signs), symptom, or disease temporally associated with the use of remimazolam, whether or not considered related to the remimazolam.

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

[0135] Definition of Serious Adverse Events

[0136] An SAE is defined as any untoward medical occurrence or effect in a clinical trial subject administered a pharmaceutical product and may or may not have a causal relationship with this treatment and which is serious (i.e. results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect or is otherwise medically important, i.e. may jeopardise the subject or may require an intervention to prevent one of the above characteristics / consequences). SAEs include all serious events independent of whether they have a suspected causal relationship to the remimazolam or not.

[0137] Definition of Serious Adverse Reaction (SAR)

[0138] A Serious Adverse Reaction (SAR) is any noxious and unintended response to an remimazolam related to any dose administered and that at any dose results in death, is lifethreatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect or is otherwise medically important (may jeopardise the subject or may require an intervention to prevent one of the above characteristics / consequences). This implies a reasonable possibility of a causal relationship between the event and the remimazolam, i.e. evidence to suggest a causal relationship.

[0139] A ‘suspected’ SAR refers to individual SAE case reports from clinical trials where a causal relationship between the SAE and the remimazolam was suspected. All individually reported SARs are considered suspected.

[0140] Definition of Unexpected Adverse Reaction

[0141] An Unexpected Adverse Reaction is defined as an AR, the nature or severity of which is not consistent with the applicable product information (e.g., IB for an unauthorised investigational product or summary of product characteristics for an authorised product).

[0142] A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a SAR which occurs in a clinical trial, and is not included in the list of expected SARs in the IB (unexpected).

[0143] Classification of an Adverse Event

[0144] Severity of Event

[0145] Severity is assessed using the below three categories:Mild: Events require minimal or no treatment and do not interfere with the participant’s daily activities.Moderate: Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interference with functioning.Severe: Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.

[0146] For all out of range laboratory values the severity grading will also be evaluated.

[0147] Relationship to Trial Medication

[0148] The following binary system for causality assessment shall be used for classifying suspected relationship of AEs to remimazolam:Related: There is a reasonable possibility that the remimazolam caused the adverse event Not related: There is no reasonable possibility that the remimazolam causes the adverse event.

[0149] ‘ Reasonable possibility’ means there is evidence to suggest a causal relationship between the remimazolam and the adverse event.

[0150] Outcome

[0151] The outcome of an AE will be classified as:Resolved: The patient has recovered completely, and no symptoms remain Resolved with sequelae: The patient has recovered, but some symptoms remain Resolving: The patient’s condition is improving, but symptoms remainNot resolved: The patient’s condition has not improved and the symptoms are unchanged or worseningDeath (Death should only be selected as outcome when the AE results in death. If more than 1 AE is possibly related to the patient’s death, the outcome of death should be indicated for each such AE.)

[0152] Adverse Event of Special Interest (AESI)

[0153] The following clinically notable changes in vital signs or requirement for manual or mechanical ventilation shall be reported as AESIs if they have a probable relationship to remimazolam. These will be analysed separately:Decreased oxygen saturation: hypoxia is defined as SpCh <92% or below 5% of preoperative baseline for >1 minute, or any drop necessitating an intervention;Clinically relevant bradycardia: defined as a heart rate that is below the absolute (1stcentile) values per age group as in Table 11; or a drop of >35% in heart rate from the baseline value recorded at screeningHypotension defined as per Table 11.Respiratory depression (values for defining respiratory depression as an AESI by age category are found Table 11);Any manual or mechanical ventilation via mask ventilation, LMA / IGEL, or endotracheal tube.

[0154] AESIs will be monitored and recorded from the start of remimazolam until the patient is fit for discharge.Table 11 Criteria for Adverse Events of Special Interest* Adapted from Bradycardia definition in the work of Larsson et al., (Larsson, P.G., et al., Incidence of bradycardia at arrival to the operaring room after oral or intravenous premedication with clonidine in children. Paediatr Anaesth., 2015. 25: p. 956-962), Mason and Lonqvist, (Mason, K.P. and Lonnqvist, P.-A, Bradycardia in perspective-not all reductions in heart rate need immediate intervention. Paediatr Anaesth., 2015. 25: p. 44-51), Values below the 1st centile identified in the work 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: p.1011-1018), are defined as bradycardia.** In accordance with hypotension definition proposed in Nafm et al. (Nafiu, O.O., et al. How do pediatric anesthesiologists define intraoperative hypotension? Paediatr. Anaesth., 2009. 19: p. 1048-1053)* * * Adapted from bradypnea definition 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 assess the efficacy of intravenous remimazolam in inducing and maintaining suitable sedation levels for pediatric patients undergoing diagnostic and / or therapeutic procedures.

[0157] Primary objective will be assessed using the following primary endpoint variables as well as their level of measurement (Table 12)Table 12 Primary endpoint variables

[0158] The primary endpoint consists of ALL 3 components. The primary endpoint is met (i.e. the treatment is considered successful for the patient) when:Completion of procedure = yes ANDNo requirement for a rescue sedative medication = yes ANDNo requirement for more than the permitted remimazolam bolus or infusion regime = yes.

[0159] Analysis of the Secondary Endpoints

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

[0161] The following table outlines the variables used to establish the secondary objectives as well as their level of measurement (Table 13).Table 13 Secondary endpoint variablesDetails regarding the instruments used in this table can be found in section 8.0 and following regarding efficacy measurements as well as safety assessments.** Possibly Ordinal based on response patterns.* * * Further PK analyses are described in a separate PK SAP.

[0162] In the table above, five point scales will be considered at the interval level of measurement resulting in the reporting of means and standard deviation for each scale or subscale. However, due to the limited sample size expected in the per cohort analysis, if three or four point scales are observed the values will be treated as ordinal in nature.

[0163] All measures that are recorded on a single occurrence will be reported as mean ± standard deviation or count and percent within category depending upon the statistical level of the variable. All of the reporting for these variables will be placed in sequential order based upon when the assessments occur. Since most scales are administered only on one occasion efficacy for primary and secondary objectives will be based upon this reporting. Currently, there are no thresholds for efficacy for the scales or variables used and no statistical testing is planned.

[0164] All categories of serious adverse events will be reported in separate tables after the conclusion of the trial for each sequential age group enrolled.

[0165] PK analysis

[0166] Levels of sedation, as defined clinically, will be compared against PI parameters of Cmax, Cx, Ctau, AUCx, (where x are other available timepoints). Results of the PK analysis will be presented in both tabular and graphical forms over applicable time points.Example 2: PK / PD Modeling Study

[0167] Methods: 31 patients > 6 years and < 18 years of age were included in the trial. Patients were stratified across 4 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 tables, below:Remimazolam doses for 16 of 31 subjectsRemimazolam doses for 15 of 31 subjects

[0168] The University of Michigan Sedation scale was used to assess the level of sedation. Blood samples were drawn to measure remimazolam and CNS7054, the main metabolite of remimazolam. Population pharmacokinetic pharmacodynamic modelling was performed in NONMEM®. Optimization of the dosing regimen and power / sample size calculations were performed in R®.

[0169] A joint population pharmacokinetic model was developed describing the concentrationtime profile of remimazolam and CNS7054 (remimazolam metabolite) in the absence or presence of fentanyl. Size-adjusted typical PK parameters were similar to PK parameters 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, described the observed UMSS well. The steady-state exposure response relationship according to the model is shown in Figure 1. Clinical trial simulations showed that the dosing regimen which was tested in the 31 -subject trial was unlikely to lead to appropriate sedation in a large proportion of patients. According to the PK / PD model, an more appropriate dosing regimen would consist of higher per kg remimazolam bolus doses (200 vs. 150 mcg.kg-1) and infusion rates (up to 80 instead of 20 mcg. kg- 1. min- 1), an extended titration scheme for continuous infusion dosing (10 - 80 instead of 7.5 - 20 mcg.kg-1. min- 1), shorter inter-dose intervals for top- up bolus doses (at least 2 min gap vs. 3 min gap between bolus doses), removal of the maximum dose cap which had been based on adult dosing and a more frequent fentanyl co-administration at higher (per kg) bolus doses (2 mcg.kg-1 vs. 1 mcg.kg-1). Clinical trial simulations suggested that a trial with 30 patients >3 years and <18 years receiving this more appropriate dosingregimen would have a high probability of demonstrating that >70 % of patients achieve a UMSS >3 15 min after the first remimazolam bolus dose.

[0170] This modelling study suggests that the pharmacokinetics of remimazolam are likely not different between children >6 years old and adults (after correcting for size differences). The pharmacodynamics between children and adults may be different, but the difference may be in part (or wholly) due to the deeper desired level of sedation for children as compared to adults for procedural sedation. The exposure response relationship suggests that the dosing regimen studied in the 31 -subject trial would be insufficient to meet the protocol specified primary endpoint. In order to effectively use remimazolam for procedural sedation in children >6 years higher remimazolam exposures will be required.

[0171] While the present disclosure has illustrated by description several embodiments and while the illustrative embodiments have been described in considerable detail, it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications may readily appear to those skilled in the art. Furthermore, features from separate lists can be combined; and features from the examples can be generalized to the whole disclosure.

[0172] List of AbbreviationsAE Adverse EventAESI Adverse Event of Special InterestASA American Society of AnesthesiologistsAUC Area under the curveBMI Body mass indexBP Blood pressure bpm Beats per minuteCES1 Carboxylesterase- 1 ACONSORT Consolidated Standards of Reporting TrialsDMC Data Monitoring CommitteeECG Electrocardiogram eCRF Electronic case report formEMA European Medicine AgencyEtC02 End-tidal C02EtN2O End-tidal Nitrous OxideEU European UnionFDA United States Food and Drug AdministrationFPFV / FPI First patient first visit / first patient inGCP Good Clinical PracticeIB Investigator’s BrochureICF Informed consent formICH International Council on Harmonisation of Technical Requirements forPharmaceuticals for Human UseIEC Independent ethics committeeIMP Investigational medicinal productIV IntravenousIxRS Interactive Response SystemLMA / IGEL / ETT Laryngeal mask airway / IGEL / Endotracheal tubeLPLV / LPO Last patient last visit I last patient inMedDRA Medical Dictionary for Regulatory ActivitiesNISS Nurse Interpretation of Sedation ScaleNRS Numerical rating scalePAED Pediatric anaesthesia emergence deliriumPD Pharmacodynamic(s)PIP Pediatric Investigation PlanPK Pharmacokinetic(s)SAE Serious adverse eventSAP Statistical analysis planSAR Serious Adverse ReactionSOP Standard operating procedureSpO2 % of oxygen saturated haemoglobinSUSAR Suspected Unexpected Serious Adverse ReactionTEAE Treatment-emergent adverse eventTFLs Tables, Figures, ListingsUMSS University of Michigan Sedation ScaleUS United StatesASPECTSAspect 1. A method of sedating a pediatric subject comprising: administering intravenously to the subject 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H- imidazol[l,2-a][l,4]benzodiazepine-4-yl]-propionic methyl ester of formula (I)(I)or a pharmaceutically acceptable salt thereof.Aspect 2. The method of Aspect 1, wherein the initial dose is in an amount of 100 to 500 mcg / kg.Aspect 3. The method of Aspect 1, further comprising administering to the subject at least one supplemental dose given after the initial dose or a previous top-up dose the compound of formula (I), or a pharmaceutically acceptable salt thereof.Aspect 4. The method of Aspect 2, wherein the at least one supplemental dose is administered not less than 2 minutes after the initial dose or a previous top-up dose.Aspect 5. The method of Aspect 4, wherein the at least one supplemental dose is administered not less than 2 minutes after the initial dose.Aspect 6. The method of Aspect 1, wherein the pharmaceutically acceptable salt is a besylate salt.Aspect 7. The method of Aspect 1, wherein the pediatric subject is sedated for less than 30 minutes.

Claims

CLAIMSWhat is claimed is:

1. A method of sedating a pediatric subject during a procedure comprising: intravenously administering to the subject 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H- imidazol[l,2-a][l,4]benzodiazepine-4-yl]-propionic methyl ester of formula (I) (remimazolam) besylate(02. The method of claim 1, wherein the initial dose of the remimazolam besylate is a bolus dose.

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

4. The method of any one of the preceding claims, wherein the initial dose is a bolus dose in an amount of about 200 mcg / kg of remimazolam free base.

5. The method of any one of the preceding claims, wherein the initial bolus dose is administered over about 1 minute.

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

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

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

9. The method of 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 start of the procedure.

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

11. The method of 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 of any one of claims 6 to 11, wherein the at least one supplemental dose is administered at least 3 minutes after the initial dose.

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

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

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

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

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

18. The method of 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 of any one of claims 15 to 18, wherein the third supplemental dose is administered at least 3 minutes after the second supplemental dose.

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

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

22. The method of any one of claims 20 to 21 further comprising increasing the infusion dose stepwise.

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

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

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

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

27. The method of any one of claims 22 to 26, wherein the stepwise increase is administered after at least 3 minutes after the initial bolus dose.

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

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

30. The method of 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 of any one of the preceding claims, wherein the patient’s sedation is a Nurse Interpretation of Sedation Score (NISS) of about 2.

32. The method of any one of the preceding claims, wherein the procedure lasts 2 hours or less.

33. The method of any one of the preceding claims, wherein the procedure is an endoscopy, a lumbar puncture, bone marrow aspiration, imaging, a dental procedure, a changing of a painful dressing, a post-surgical procedure requiring sedation, cardiac catheterization, or central venous catheter insertion.

34. The method of any one of the preceding claims, wherein the procedure is a nerve block, central venous catheter removal, or awake intubation.

35. The method of any one of the preceding claims, wherein the procedure is completed.

36. The method of any one of the preceding claims, wherein the procedure does not require administration of a rescue sedative mediation.

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