Investigation of Remimazolam in Children Undergoing Sedation for Medical Procedures

Study Overview
=================
Brief Summary
-----------------
To assess the efficacy of intravenous remimazolam in inducing and maintaining suitable sedation levels for paediatric patients undergoing diagnostic and/or therapeutic procedures

Detailed Description
-----------------
This trial is part of the European Paediatric Investigational Plan and the US Pediatric Study Plan and has been developed in line with guidance from the EMA Paediatric Committee and the US FDA. The trial will commence with cohort 1 (aged ≥6 and <18 years) and proceed to lower age groups: cohort 2 (≥3 and <6 years); and, in European sites only, cohort 3 (full-term birth to <3 years). The Data Monitoring committee (DMC) may convene any time after at least half of the subjects in cohort 1 or 2 have completed the study, to review PK,safety and efficacy data. If there are no concerns, the DMC may recommend to initiate concurrent dosing in the next younger cohort (cohort 2 or 3) in parallel to dosing the remaining subjects in cohort 1 or 2 Dosing for cohort 3 will be predicted based on PK modelling as well as efficacy and safety outcomes of the older age groups. Enrolment of patients aged <2 years will not be permitted until supported by adequate juvenile toxicity data. The trial will consist of three visits: Screening (Day -21 to day 1),Treatment (Day 1), and Follow-up (Day 4 [+3/-1 days]).

Official Title
-----------------
A Phase 2/3, Prospective, Open-label Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of Remimazolam for Intravenous Sedation in Paediatric Patients Undergoing Diagnostic and/or Therapeutic Procedures

Conditions
-----------------
Pediatric ALL

Intervention / Treatment
-----------------
* Drug: Remimazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form and/or assent and willingness of patient and parent(s) to participate in the trial. In US sites: Paediatric male or female patients, aged ≥3 and <18 years scheduled to undergo a diagnostic or therapeutic procedure, which is medically indicated and independent from the trial. In European sites: Paediatric male or female patients, aged full term birth to <18 years scheduled to undergo a diagnostic or therapeutic procedure, which is medically indicated and independent from the trial. Maximum planned duration of procedure: 2 hours ASA Physical Status I-III Planned spontaneous breathing during sedation 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 specified observations are completed) Negative pregnancy test at screening and on treatment day - Exclusion Criteria: Emergency procedures Condition/procedure that requires planned airway control via endotracheal tube or LMA/IGEL insertion Cranio-facial malformation, which would severely limit the possibilities for emergency airway rescue Other abnormalities relating to the airway (including large tonsils and anatomical abnormalities of upper airway or lower airway) which may compromise emergency airway rescue Known hypersensitivity to benzodiazepines, flumazenil, dextran or any of the ingredients of the drug product Known paradoxical reactions to benzodiazepines History of sleep apnoea Active respiratory failure Active neuromuscular disease Active cardiac failure Active hepatic failure Breast feeding females Prohibited medication Any patient judged by the Principal Investigator (PI) or Sub-Investigator to be inappropriate for the trial for any other reason

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: A Phase 2/3 prospective, open-label trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Patients<br>All paediatric patients undergoing diagnostic and/or therapeutic procedures | Drug: Remimazolam<br>* Remimazolam for intravenous sedation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of the procedure | Success of the procedure defined as: Completion of the procedure AND no requirement for rescue sedative medication AND no requirement for more than the permitted bolus or infusion regimen | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target depth of sedation achieved | Proportion of patients achieving predefined target depth of sedation (assessed using University of Michigan Sedation Score [UMSS]) during procedure | 2 hours | 
| Target range of sedation achieved during 80% of procedure duration | Proportion of patients in whom predefined target range of sedation (assessed using University of Michigan Sedation Score [UMSS]) was achieved during at least 80% of procedure duration | 2 hours | 
| Percentage of time within target range of sedation | Percentage of time spent by patients within predefined target range of sedation (assessed using University of Michigan Sedation Score [UMSS]) during procedure | 2 hours | 
| Adequacy of sedation | Depth of sedation (assessed using Nurse Interpretation of Sedation Scale [NISS]) of patients over time | 2 hours | 
| Time to start of procedure | Time between initial administration of study drug and start of procedure | 2 hours | 
| Time to fully alert | Time between last dose of study drug, end of procedure and full alertness, defined as the first of three consecutive sedation scores showing no sedation | 2 hours | 
| Time to ready for discharge | Time between last dose of study drug, end of procedure and discharge readiness | 2 hours | 
| Signs of re-sedation | Occurrence, after reaching a University of Michigan Sedation Score (UMSS) of 0 after end of procedure, of a UMSS greater than zero | 2 hours | 
| Procedure success excluding cases where the procedure could not be completed for non sedative reasons | Success of the procedure defined as: Completion of the procedure AND no requirement for rescue sedative medication AND no requirement for more than the permitted bolus or infusion regimen; excluding any patients where procedure was not completed for reasons other than failure of sedation | 2 hours | 
| Safety: AEs | Incidence of treatment-emergent adverse events | 4 days | 
| Safety: emergence of delirium | Incidence of paediatric anaesthesia emergence delirium between end of procedure until fit for discharge | 2 hours | 
| Safety: need for ventilation | Incidence of use of any manual or mechanical ventilation | 2 hours | 
| Safety: need for reversal | Incidence of use of flumazenil for reversal of benzodiazepine effect | 2 hours | 
| PK: assessment of plasma concentration-time relationship | Graphical description of plasma concentration over time and comparison to predicted concentration-time relationship as calculated from existing pharmacokinetic/pharmacodynamic model | 3.5 hours |