The Use of ADV6209 for Premedication in Pediatric Anesthesia

Study Overview
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Brief Summary
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To evaluate the effect of ADV6209, a new oral Midazolam formulation, on preoperative anxiety and sedation levels in paediatric anaesthesia Primary Objective: Sedation score (mYPAS) 30 min after administration of the premedication drug Secondary Objective: Acceptance of anaesthesia mask induction Acceptance of oral administration of the premedication drug

Detailed Description
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Premedication represents an important part in the perioperative management of children and is used to reduce pre-operative stress as well as to facilitate induction of inhaled anaesthesia. Midazolam is the drug most often used for premedication in infants and children because it provides good sedation, anxiolytic and amnestic effects and few side effects. Oral intake of the drug is the most preferred route of administration by paediatric patients, whereas the majority of existing oral Midazolam solutions involve the use of i.v. Midazolam formulation given orally, unregistered or off-label. Moreover i.v. Midazolam solutions are often not well accepted by children because of their bitter taste. Considering the lack of available oral medications for moderate sedation in children in most European countries, ADV6209, an innovative 0.2% (w/v) oral solution of Midazolam for children from six months of age, was developed. The formation of a γ-Cyclodextrin -Midazolam complex, representing a new chemical formula, was used to improve the solubility and the palatability of the Midazolam formulation. A pharmacokinetic (PK) study has been executed in adults, children and adolescents, whereas ADV6209 showed improvements to current extemporaneous oral solutions of midazolam (EOM) preparations in terms of taste and easiness of use while presenting a similar PK profile. Satisfying sedation, measured with the Observer Assessment of Alertness/Sedation Scale (OAA score / S≤17) was observed in 78.4% of paediatric patients 30 minutes after ADV6209 administration. Anxiety score (modified Yale Preoperative Anxiety Scale - mYPAS) was decreased by 18.3% on average over baseline, 30 minutes after ADV6209 with a more pronounced effect in the youngest children who were also the most anxious prior to administration of the drug. In general the treatment was well accepted by all children and did not induce more crying and nausea / vomiting than before Midazolam. ADV6209 seems a very promising premedication drug. It has been licensed by the EU regulatory authorities to become the first licensed paediatric sedative in the EU (September 2018). It may help to avoid unregistered and off label use of EOM. Consequently, we want to evaluate the efficacy and safety of ADV6209 on preoperative anxiety and sedation levels in paediatric anaesthesia in daily clinical routine in this randomized, controlled, double blinded study.

Official Title
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The Use of ADV6209 for Premedication in Pediatric Anesthesia: a Controlled, Randomized, Double Blinded Study

Conditions
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Preanesthetic Medication

Intervention / Treatment
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* Drug: ADV6209 (=gamma-cyclodextrin-Midazolam)
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ASA 1 and 2 children from 2-8 years scheduled for elective surgical or diagnostic procedures, where premedication would be used in clinical routine Signed written parental informed consent prior to inclusion in the study Exclusion Criteria: ASA 3-5 Allergy against the study drug Participation in another clinical study investigating another IMP within one month prior to screening Other objections to study participation in the opinion of the investigator Parent's or legal guardian's refusal of participation of the child

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A controlled, randomized, double blinded study Study group 1 (40 children) ADV6209 0.25 mg/kg p.o. Study group 2 (40 children) Midazolam (in orange flavoured syrup) 0.25 mg/kg p.o.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADV6209<br>ADV6209 (= gamma-cyclodextrin-Midazolam) 0.25 mg/kg p.o. once 30 min. before anesthesia | Drug: ADV6209 (=gamma-cyclodextrin-Midazolam)<br>* 30 min. before anesthesia children have to swallow the anxiolytic drug (ADV6209)<br>* Other names: Ozalin (registered Tradename);|
| Active Comparator: Midazolam<br>Midazolam (in orange flavored syrup) 0.25 mg/kg p.o. once 30 min. before anesthesia | Drug: Midazolam<br>* 30 min. before anesthesia children have to swallow the anxiolytic drug Midazolam<br>* Other names: Dormicum (Tradename);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of the sedation score (modified Yale Preoperative Anxiety Scale - mYPAS-short form) at 30 minutes after administration of the premedication drug | The mYPAS-SF consists of four items (activity, vocalizations, emotional expressivity and state of apparent arousal). Each domain consists of Likert-type response options reflecting behaviours. Children's behaviour is rated from 1 to 4 or 1 to 6 (depending on the domain), with higher numbers indicating the highest severity within that domain | The level of sedation 1 minute before the premedication will be graded and compared to the level of sedation 30 minutes after the oral administration of the drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptance of oral administration of the premedication drugs | Observers record the child's acceptance of the orange-flavoured γ-Cyclodextrin -Midazolam (Ozalin®) (intervention group) or the Midazolam in orange - flavoured syrup (control group) according to the following graduation immediately after administration of the study drug: (1) The child accepts readily, (2) the child accepts with facial grimace, (3) the child accepts with verbal complaint or (4) the child rejects entirely or spits out almost/or all of the dose. | Will be evaluated, when the children swallow the premedication drug - 30 minutes before the induction of anaesthesia | 
| Acceptance of anaesthesia mask induction | Mask Acceptance Score: A four-point mask-induction score will be used to determine the quality of induction of narcosis via face mask as follows: (1) Very good, immediate acceptance of the face mask, (2) good, slight resistance, (3) moderate, struggle against face mask and (4) difficult, moderate force necessary. | Will be evaluated, when anaesthesia is induced with the anesthesia mask - 30 minutes after the premedication |