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

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

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

Study Overview

• Status: Completed
• Conditions: ICU Sedation
• Intervention / Treatment: Drug: Dexmedetomidine hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Kyoto, Japan, 602-8566
    • University Hospital, Kyoto Prefectural University of Medicine
  • Okayama, Japan, 700-8558
    • Okayama University Hospital
  • Osaka, Japan, 534-0021
    • Osaka City General Hospital
  • Shizuoka, Japan, 420-8660
    • Shizuoka Children's Hospital
  • Hokkaido
    • Asahikawa, Hokkaido, Japan, 078-8510
      • Asahikawa Medical University Hospital
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0047
      • Hyogo Prefectural Kobe Children's Hospital
  • Kagawa
    • Zentsuji, Kagawa, Japan, 765-8507
      • Shikoku Medical Center for Children and Adults
  • Osaka
    • Izumi, Osaka, Japan, 594-1101
      • Osaka Women's and Children's Hospital
    • Takatsuki, Osaka, Japan, 569-8686
      • Osaka Medical College Hospital
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0498
      • Jichi Medical University Hospital
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Juntendo University Hospital
    • Fuchu, Tokyo, Japan, 183-8561
      • Tokyo Metropolitan Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 months to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. Subjects aged ≥45 weeks CGA to <17 years old at time of consent. No restriction on sex of subject.
3. [Elective surgical cases] Subjects classified as American Society of Anesthesiologists (ASA) (ASA physical status classification) Class I to III by preoperative diagnosis.
4. [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.
5. [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.
6. If a subject is a female of childbearing potential, she should not be pregnant or possibly pregnant, or lactating.

Exclusion Criteria:

1. 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.
2. Subjects with 2nd or 3rd degree heart block during the tests at the screening visit (excluding subjects using a pacemaker).

3. 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
4. Subject of bradycardia (≤10th centile of heart rate for healthy children) during the physical examination at screening period.
5. Subjects with ALT ≥100 U/L during the laboratory tests at the screening visit.
6. 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.
7. Subjects who may need a sedative or analgesic (including narcotics) other than dexmedetomidine, midazolam or fentanyl during treatment with the investigational product.
8. Subjects who have acute febrile illness [with a temperature (core or tympanic) ≥ 38.0°Centigrade] at the screening visit.
9. 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.
10. Subjects who received dexmedetomidine within 48 hours before baseline.
11. 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.
12. 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).
13. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: DA-9501; 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; 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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment- Emergent Adverse Events (AE) and Serious Adverse Events (SAE)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to up to 28 days after end of study drug dosing (up to 56 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious adverse events (AEs) and SAEs.	Baseline up to 28 days after end of study drug dosing (up to 56 days)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Vital signs included: systolic and diastolic blood pressure, heart rate, respiratory rate, percutaneous oxygen saturation, end-tidal carbon dioxide, core body temperature and body weight. Criteria for clinically significant vital signs abnormalities was based on Investigators decision.	Baseline up to 28 days after end of study drug dosing (Day 56)
Number of Participants With Laboratory Test Abnormalities	Criteria for abnormality: hemoglobin, hematocrit and red blood cell count <0.8*lower limit of normal(LLN); platelet <0.5*LLN; >1.75*upper limit of normal(ULN); white blood cell count <0.6*LLN; >1.5*ULN; lymphocytes, neutrophils and stab cells <0.8*LLN; >1.2*ULN; eosinophils, basophils and monocytes >1.2*ULN; total bilirubin >1.5*ULN; aspartate aminotransferase, alanine aminotransferase and gamma guanosine triphosphate and alkaline phosphatase >3*ULN; total protein and albumin <0.8*LLN; >1.2*ULN; glucose <0.6*LLN; >1.5*ULN; blood urea nitrogen and creatinine >1.3*ULN; uric acid >1.2*ULN; sodium <0.95*LLN; >1.05*ULN, potassium, calcium and magnesium <0.9*LLN; >1.1*ULN; phosphate <0.8*LLN; >1.2*ULN.	Baseline up to 28 days after end of study drug dosing (Day 56)
Total Input/Output Fluid Volume	Total input fluid volume was defined as the quantity of total fluids administered and total output fluid volume was defined as the quantity of total fluids excreted or lost during the specified evaluation period.	Baseline up to 28 days after end of study drug dosing (Day 56)
Incidence of Potential Withdrawal Symptoms	The potential withdrawal symptoms were defined as AEs that occurred or worsened after end of administration of dexmedetomidine. It included bradycardia, abdominal discomfort, abdominal pain, dry mouth, nausea, vomiting, injection site pain, pyrexia, body temperature increased, electrocardiogram QT prolonged, neuralgia, agitation, atelectasis, oropharyngeal pain and hypotension. Incidence of potential withdrawal symptoms was reported in terms of number of participants who had any of the mentioned withdrawal symptoms.	Baseline up to 28 days after end of study drug dosing (Day 56)
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	Criteria for clinically significant electrocardiogram abnormalities was based on Investigators decision.	Baseline up to 28 days after end of study drug dosing (Day 56)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Maruishi Pharmaceutical

Publications and helpful links

General Publications

• Takeuchi M, Nemoto S, Suzuki Y, Takahashi N, Takenaka N, Takata A, Kobayashi M. Age-Specific Dose Regimens of Dexmedetomidine for Pediatric Patients in Intensive Care Following Elective Surgery: A Phase 3, Multicenter, Open-Label Clinical Trial in Japan. Pediatr Crit Care Med. 2021 Nov 1;22(11):e546-e557. doi: 10.1097/PCC.0000000000002730.

Helpful Links

• To obtain contact information for a study center near you, click here.
• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2016
• Primary Completion (Actual): May 24, 2017
• Study Completion (Actual): May 24, 2017

Study Registration Dates

• First Submitted: April 11, 2016
• First Submitted That Met QC Criteria: April 27, 2016
• First Posted (Estimate): May 2, 2016

Study Record Updates

• Last Update Posted (Actual): December 17, 2018
• Last Update Submitted That Met QC Criteria: May 16, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: C0801017; ZIN-DEX-1506 (Other Identifier: Alias Study Number)