Study of DA-9501 In Pediatric Subjects In The Intensive Care Unit

Study Overview
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Brief Summary
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To evaluate the efficacy, safety, and pharmacokinetics of dexmedetomidine given as continuous IV infusion in pediatric subjects [≥ 45 weeks CGA (corrected gestational age) to <17 years old] requiring sedation under intensive care unit

Official Title
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Phase 3, Multi-center, Single-arm, Open-label Study Evaluating The Efficacy, Safety, And Pharmacokinetics Of Da-9501 (Dexmedetomidine Hydrochloride) In Pediatric Subjects In The Intensive Care Unit

Conditions
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ICU Sedation

Intervention / Treatment
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* Drug: Dexmedetomidine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects whose consent is obtained in writing prior to the clinical trial from a guardian after a full explanation. For subjects over 7 years old, it is desirable that an informed assent is also obtained from the pediatric subject him/herself when possible. Subjects aged ≥45 weeks CGA to <17 years old at time of consent. No restriction on sex of subject. [Elective surgical cases] Subjects classified as American Society of Anesthesiologists (ASA) (ASA physical status classification) Class I to III by preoperative diagnosis. [Elective surgical cases] Subjects who require at least 6 hours of respiratory management with intubation under intensive care from immediately after surgery and are anticipated to require sedation. [Medical ICU cases] Subjects who require at least 24 hours of respiratory management with intubation under intensive care and are anticipated to require sedation. For medical ICU cases, sedatives used prior to treatment with the investigational product should be discontinued before the start of treatment with the investigational product. If a subject is a female of childbearing potential, she should not be pregnant or possibly pregnant, or lactating. Exclusion Criteria: Subjects who are judged by investigator or sub-investigator to have a neurological disease that will make sedation assessment difficult, such as: Subjects with brain damage which is expected to increase intracranial pressure due to trauma or central nervous system disease Subjects with cerebral palsy, autism, severe mental retardation, etc. Subjects with paralysis due to continuous administration of a muscle relaxant or due to a spinal injury of class T5 or higher. Subjects with 2nd or 3rd degree heart block during the tests at the screening visit (excluding subjects using a pacemaker). Subjects with any of the following low blood pressure levels during the tests at the screening visit: Age ≥ 45 weeks CGA to < 1 year old: Systolic Blood Pressure (SBP) <70 mmHg Age ≥ 1 year old to < 10 years old: SBP < 70 + (2 x age in years) mmHg Age ≥ 10 years old to < 17 years old: SBP < 90 mmHg Subject of bradycardia (≤10th centile of heart rate for healthy children) during the physical examination at screening period. Subjects with ALT ≥100 U/L during the laboratory tests at the screening visit. Subjects in whom dexmedetomidine or other alfa 2 receptor agonists, alfa 2 receptor antagonists and drug that may be used in this study are contraindicated. Subjects who may need a sedative or analgesic (including narcotics) other than dexmedetomidine, midazolam or fentanyl during treatment with the investigational product. Subjects who have acute febrile illness [with a temperature (core or tympanic) ≥ 38.0°Centigrade] at the screening visit. Subjects who received other investigational product within 30 days before baseline or subjects who will participate in other study that uses an investigational product during the study period. Subjects who received dexmedetomidine within 48 hours before baseline. Subjects who, in the opinion of the investigator or sub-investigator, may be at increased risk to the subject due to the conduct of the study or may have a disease or factor which will probably preclude the obtainment of sufficient study data. Subjects for whom, in the opinion of the investigator or sub-investigator, risks involved with administration of dexmedetomidine outweigh its benefits (e.g., >2 doses of vasopressor due to cardiogenic shock). Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Sponsor's employees directly involved in the conduct of the study.

Ages Eligible for Study
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Minimum Age: 45 Weeks
Maximum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DA-9501<br>A single vial contains an injection solution with 2 mL of dexmedetomidine hydrochloride solution (100 µg/mL as dexmedetomidine) dissolved in physiological saline | Drug: Dexmedetomidine hydrochloride<br>* 45 weeks CGA to < 6 years old: Maintenance infusion will be started at 0.2 µg/kg/h. The infusion rate will be adjusted within a range of 0.2 to 1.4 µg/kg/h according to the pediatric subject's sedative state 6 years old to < 17 years old: Maintenance infusion will be started at 0.2 µg/kg/h. The infusion rate will be adjusted within a range of 0.2 to 1.0 µg/kg/h according to the pediatric subject's sedative state<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Did Not Require a Rescue Sedative Within 24 Hours of Dosing of Study Drug | Percentage of participants who did not require rescue medication for Sedation (Midazolam) based on the data of investigator's judgement and State Behavioral Scale (SBS) (which was a sedation assessment instrument for intubated participants and its score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= unresponsive. During intubation [placement of a flexible plastic tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs], the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation [removal of endotracheal tube], the target sedation depth was -1 to 0, where higher score indicated more responsive) were reported. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Did Not Require Administration of a Rescue Analgesic Within 24 Hours of Dosing of Study Drug | Percentage of participants who did not require administration of a rescue analgesic (Fentanyl) in addition to administration of the study drug based on investigator's judgement were reported. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Total Amount of Rescue Sedative Administered Within 24 Hours of Dosing of Study Drug | Total amount of rescue sedative (midazolam) administered Within 24 Hours of dosing of study drug. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Body Weight Adjusted Total Amount (Per Kg) of Rescue Sedative Taken Within 24 Hours of Dosing of Study Drug | Total amount of rescue sedative (midazolam) required within 24 hours of dosing of study drug. Dose was adjusted for body weight (mg divided by kg). | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Total Amount of Rescue Analgesic Taken Within 24 Hours of Dosing of Study Drug | Total amount of rescue sedative (fentanyl) required Within 24 Hours of dosing of study drug. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Body Weight Adjusted Total Amount of Rescue Analgesic Taken Within 24 Hours of Dosing of Study Drug | Total amount of rescue analgesic (fentanyl) within 24 Hours of dosing of study drug. Dose was adjusted for body weight (mcg divided by kg). | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Duration of Maintenance of Target Sedation Level Within 24 Hours of Dosing of Study Drug | Time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the SBS. SBS was a sedation assessment instrument for intubated participants and its score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= unresponsive. During intubation (placement of a flexible plastic tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs), the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation (removal of endotracheal tube), the target sedation depth was -1 to 0, where higher score indicated more responsive. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Percentage of Maintenance Duration of Target Sedation Level Within 24 Hours of Dosing of Study Drug | Percentage of time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the state behavioral scale (SBS). SBS is a sedation assessment instrument and it's score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= non-responsive. During intubation the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation, the target sedation depth was -1 to 0, where higher score indicated more responsive. | From start of study drug administration on Day 1 up to 24 hours of study drug dosing or at the conclusion of mechanical ventilation or the end of study drug administration, whichever is earliest (up to maximum of 28 days) | 
| Percentage of Participants Who Did Not Use a Rescue Sedative After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Percentage of participants whose period of dosing of the investigational product exceeded 24 hours and who did not received rescue medication for Sedation (Midazolam) based on the data of investigator's judgement and SBS (which was a sedation assessment instrument for intubated participants and its score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= unresponsive. During intubation [placement of a flexible plastic tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs], the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation [removal of endotracheal tube], the target sedation depth was -1 to 0, where higher score indicated more responsive) were reported. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Percentage of Participants Who Did Not Require Dosing of a Rescue Analgesic After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Percentage of participants whose period of dosing of the investigational product exceeded 24 hours and who did not received rescue analgesic (Fentanyl) based on the investigator's judgement were reported. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Total Amount of Rescue Sedative Taken After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Total amount of rescue sedative (midazolam) administered after 24 hours of dosing of study drug. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Body Weight Adjusted Total Amount of Rescue Sedative Taken After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Total amount of rescue sedative (midazolam) required after 24 hours of dosing of study drug. Dose was adjusted for body weight (mg divided by kg). | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Total Amount of Rescue Analgesic Taken After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Total amount of rescue analgesic (Fentanyl) administered by the participants after 24 hours of dosing of study drug. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Body Weight Adjusted Total Amount of Rescue Analgesic Taken After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Total amount of rescue analgesic (fentanyl) after 24 hours of dosing of study drug. Dose was adjusted for body weight (mcg divided by kg). | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Duration of Maintenance of Target Sedation Level After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the state behavioral scale (SBS). SBS is a sedation assessment instrument for intubated participants and its score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= unresponsive. During intubation (placement of a flexible plastic tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs), the target sedation depth by SBS was -2 to 0, where higher score indicated more stability and after extubation (removal of endotracheal tube), the target sedation depth was -1 to 0, where higher score indicated more stability. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Percentage of Maintenance Duration of Target Sedation Level After 24 Hours of Dosing of Study Drug Till End of Mechanical Ventilation | Percentage of time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the state behavioral scale (SBS). SBS is a sedation assessment instrument and it's score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= non-responsive. During intubation the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation, the target sedation depth was -1 to 0, where higher score indicated more responsive. | After 24 hours of study drug dosing till end of mechanical ventilation (up to 28 days) | 
| Duration of Maintenance of Target Sedation Level After Extubation | Time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the state behavioral scale (SBS). SBS is a sedation assessment instrument for intubated participants and its score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= unresponsive. During intubation (placement of a flexible plastic tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs), the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation (removal of endotracheal tube), the target sedation depth was -1 to 0, where higher score indicated more responsive. | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Percentage of Maintenance Duration of Target Sedation Level After Extubation | Percentage of time duration for which the target sedation level was maintained during the specified evaluation period within participants was reported. Target sedation level was analyzed by target sedation scores by using the state behavioral scale (SBS). SBS is a sedation assessment instrument and it's score ranges from 2 to -3, where 2= agitated, 1= restless and difficult to calm, 0= awake and able to calm, -1= responsive to gentle touch or voice, -2= responsive to noxious stimuli and -3= non-responsive. During intubation the target sedation depth by SBS was -2 to 0, where higher score indicated more responsive and after extubation, the target sedation depth was -1 to 0, where higher score indicated more responsive. | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Total Amount of Rescue Sedative Taken After Extubation | Total amount of rescue sedative (Midazolam) administered by the participants after extubation. | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Body Weight Adjusted Total Amount of Rescue Sedative Taken After Extubation | Total amount of rescue sedative (midazolam) administered by the participants after extubation. Dose was adjusted for body weight (mg divided by kg). | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Total Amount of Rescue Analgesic Taken After Extubation | Total amount of rescue analgesic (fentanyl) administered by the participants after extubation. | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Body Weight Adjusted Total Amount of Rescue Analgesic Taken After Extubation | Total amount of rescue analgesic (fentanyl) administered by the participants after extubation. Dose was adjusted for body weight (mcg divided by kg). | From extubation till end of treatment (6 hours after start of study drug dosing up to 28 days) | 
| Median Time to Conclusion of Mechanical Ventilation | Time to conclusion of mechanical ventilation was defined as time duration from start of study drug administration until the end of mechanical ventilation. | Baseline (start of study drug dosing) until end of mechanical ventilation (up to 28 days) |