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The purpose of this study is to investigate the pharmacokinetic, pharmacodynamic, and safety of dexmedetomidine at 2 different dose levels in pediatric subjects, aged 12 months through <24 months, administered as an intravenous loading dose followed by continuous infusion for a minimum of 6 hours and up to 24 hours in an intensive care setting.
Phase II, randomized, open-label, single-center, study evaluating the pharmacokinetics and pharmacodynamics of dexmedetomidine in pediatric subjects across two dose levels (Dose Level 1 consists of a 0.7 mcg/kg loading dose immediately followed by a 0.5 mcg/kg/hr maintenance infusion; Dose Level 2 consists of a 1.0 mcg/kg loading dose immediately followed by a 0.75 mcg/kg/hr maintenance infusion). The study population will consist of intubated and mechanically ventilated pediatric subjects who require sedation in an intensive care setting for a minimum of 6 hours but not to exceed 24 hours. Subjects eligible for enrollment are 12 months to <24 months of age.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose level 1 | Experimental | Dexmedetomidine 0.7 mcg/kg loading dose and 0.5 mcg/kg/hr maintenance infusion |
|
| Dose level 2 | Experimental | Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance infusion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | For sedation according to protocol |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-time Curve (AUC0-∞) | Area under the plasma concentration-time curve of dexmedetomidine at 0 to Infinity hours | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Observed Peak Plasma Concentration (Cmax) | Maximum observed concentration of dexmedetomidine in plasma | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Steady State Concentration (Css) | Concentration of dexmedetomidine at steady state in plasma | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Terminal Elimination Half-life (t1/2) | Terminal elimination half-life of dexmedetomidine. Half-life is the time required for plasma concentration of the drug to decrease by 50%. | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Time to Reach Maximum Plasma Concentration (Tmax) | Observed time to reach maximum plasma concentration of dexmedetomidine, expressed in hours | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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Inclusion Criteria:
Exclusion Criteria:
Pediatric subjects with neurological conditions that prohibit an evaluation of sedation such as:
Subjects with second degree or third degree heart block unless subject has a permanent pacemaker or pacing wires are in situ.
Subjects who have hepatic impairment as defined by a serum glutamic-pyruvic transaminase/alanine aminotransferase (SGPT/ALT) >90 U/L at the time of screening.
Subjects who have hypotension, based on repeat assessments within 15 minutes preceding the start of study drug, defined as: Systolic blood pressure (SBP) <70 mmHg.
Pre-existing bradycardia based on repeated assessments within 15 minutes preceding the start of study drug, defined as: Heart rate (HR) <70 bpm.
Subject who have acute thermal burns involving more than 15 percent total body surface area.
Subjects who have a known allergy to dexmedetomidine, midazolam or fentanyl.
Subject who has received dexmedetomidine within 15 hours prior to the start of study drug.
Subjects with a life expectancy that is <72 hours.
Subjects that are expected to have hemodialysis (continuous hemofiltration), peritoneal dialysis or extracorporeal membrane oxygenation (ECMO) treatments within 48 hours prior to the start of study drug or during the duration of the study.
Subjects who have been treated with α-2 agonists/antagonists within 2 weeks.
Subjects with a spinal cord injury above T5 (5th Thoracic Vertebra).
Subjects who have received another investigational drug as part of an investigational drug study within the past 30 days.
Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of this clinical study.
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| Name | Affiliation | Role |
|---|---|---|
| Constantinos Chrysostomou, MD | Children's Hospital of Pittusburgh of UPMC | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Pittusburgh of UPMC | Pittsburgh | Pennsylvania | 15224 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose Level 1 | Dexmedetomidine 0.7 mcg/kg loading dose and 0.5 mcg/kg/hr maintenance infusion |
| FG001 | Dose Level 2 | Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance infusion |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety Evaluable Population consisted of all subjects who received any amount of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose Level 1 | Dexmedetomidine 0.7 mcg/kg loading dose and 0.5 mcg/kg/hr maintenance infusion |
| BG001 | Dose Level 2 | Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance infusion |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration-time Curve (AUC0-∞) | Area under the plasma concentration-time curve of dexmedetomidine at 0 to Infinity hours | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | picogram*hour per millilitre | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose Level 1 | Dexmedetomidine 0.7 mcg/kg loading dose and 0.5 mcg/kg/hr maintenance dose |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pyrexia | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marcelo Garcia de Rocha MD, Global Medical Director | Hospira | 224-212-4424 | marcelo.rocha@hospira.com |
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| ID | Term |
|---|---|
| D010146 | Pain |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Weight-Adjusted Plasma Clearance (CLw) | Weight-Adjusted Plasma Clearance of dexmedetomidine after intravenous administration. | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Plasma Clearance (CL) | Clearance of dexmedetomidine after intravenous administration. Clearance is the rate at which the drug is removed from the plasma after the dose. | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Volume of Distribution (Vd) | Volume of distribution of dexmedetomidine after intravenous administration. Volume of distribution measures how much the drug spreads through the body after the dose. | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Weight-Adjusted Volume of Distribution (Vdw) | Weight-Adjusted Volume of distribution of dexmedetomidine after intravenous administration. | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
| Average Total Faces, Legs, Activity, Cry, and Consolability (FLACC) Score | FLACC scale is a 5 category observational measure to assess pediatric pain on face, legs, activity, cry and consolability. Responses in each category are scored between 0 to 2 (0 = normal, relaxed to 2 = upset, rigid), for a maximum total score of 10. | Prior to loading dose and every hour during the maintenance infusion; within 5 minutes after any fentanyl administration during DEX infusion or every 4 hours in case of continuous fentanyl infusion; within 5 minutes prior and after titration of fentanyl |
| Absolute Time That Subject is in UMSS Range 2-4 During Treatment Period | The level of sedation will be assessed using the University of Michigan Sedation Scale (UMSS). Score 0 (awake/alert); Score 1 (sleepy/responds appropriately); Score 2 (somnolent/arouses to light stimuli); Score 3 (deep sleep/arouses to deeper physical stimuli); Score 4 (unarousable). The UMSS scores obtained just prior the loading dose (LD) and 5 and 10 minutes during LD; 0, 5, 10, 15, 30, and 60 minutes and thereafter every 4 hours of the maintenance infusion; within 5 minutes of obtaining each pharmacokinetic sample; within 5 minutes prior and after any midazolam rescue during dexmedetomidine infusion period. | During the treatment (6 to 24 hours) |
| Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Participants who received rescue medication midazolam for sedation and/or fentanyl for analgesic during study drug Infusion | During the treatment (6 to 24 hours) |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance infusion |
|
|
| Primary | Observed Peak Plasma Concentration (Cmax) | Maximum observed concentration of dexmedetomidine in plasma | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | picogram per millilitre | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
|
|
|
| Primary | Steady State Concentration (Css) | Concentration of dexmedetomidine at steady state in plasma | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | picogram per millilitre | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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| Primary | Terminal Elimination Half-life (t1/2) | Terminal elimination half-life of dexmedetomidine. Half-life is the time required for plasma concentration of the drug to decrease by 50%. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Hours | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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| Primary | Time to Reach Maximum Plasma Concentration (Tmax) | Observed time to reach maximum plasma concentration of dexmedetomidine, expressed in hours | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Hours | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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| Primary | Weight-Adjusted Plasma Clearance (CLw) | Weight-Adjusted Plasma Clearance of dexmedetomidine after intravenous administration. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Litre per Hours per Kilogram | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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|
| Primary | Plasma Clearance (CL) | Clearance of dexmedetomidine after intravenous administration. Clearance is the rate at which the drug is removed from the plasma after the dose. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Litre per Hour | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
|
|
|
| Primary | Volume of Distribution (Vd) | Volume of distribution of dexmedetomidine after intravenous administration. Volume of distribution measures how much the drug spreads through the body after the dose. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Litre | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
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|
|
| Primary | Weight-Adjusted Volume of Distribution (Vdw) | Weight-Adjusted Volume of distribution of dexmedetomidine after intravenous administration. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Litre per Kilogram | 30 minutes prior to loading dose (LD); 5 minutes before finishing LD; 0.5, 1, 2 and 4-6 hours during maintenance infusion (MI); 30 minutes prior (within 24 hours of start of MI) and 10 minutes, 0.5, 1, 2, 4 and 10 hours end of MI |
|
|
|
| Primary | Average Total Faces, Legs, Activity, Cry, and Consolability (FLACC) Score | FLACC scale is a 5 category observational measure to assess pediatric pain on face, legs, activity, cry and consolability. Responses in each category are scored between 0 to 2 (0 = normal, relaxed to 2 = upset, rigid), for a maximum total score of 10. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | units on a scale | Prior to loading dose and every hour during the maintenance infusion; within 5 minutes after any fentanyl administration during DEX infusion or every 4 hours in case of continuous fentanyl infusion; within 5 minutes prior and after titration of fentanyl |
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| Primary | Absolute Time That Subject is in UMSS Range 2-4 During Treatment Period | The level of sedation will be assessed using the University of Michigan Sedation Scale (UMSS). Score 0 (awake/alert); Score 1 (sleepy/responds appropriately); Score 2 (somnolent/arouses to light stimuli); Score 3 (deep sleep/arouses to deeper physical stimuli); Score 4 (unarousable). The UMSS scores obtained just prior the loading dose (LD) and 5 and 10 minutes during LD; 0, 5, 10, 15, 30, and 60 minutes and thereafter every 4 hours of the maintenance infusion; within 5 minutes of obtaining each pharmacokinetic sample; within 5 minutes prior and after any midazolam rescue during dexmedetomidine infusion period. | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters. | Posted | Mean | Standard Deviation | Hours | During the treatment (6 to 24 hours) |
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| Primary | Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Participants who received rescue medication midazolam for sedation and/or fentanyl for analgesic during study drug Infusion | Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate pharmacokinetic samples to estimate primary parameters. | Posted | Number | participants | During the treatment (6 to 24 hours) |
|
|
|
| 0 |
| 2 |
| 0 |
| 2 |
| EG001 | Dose Level 2 | Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance dose | 0 | 3 | 1 | 3 |
| Atelectasis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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