Pain, Sedation
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGDexmedetomidine
For sedation according to protocol
Sponsors
Hospira, now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 23 Months
Healthy volunteers
No
Inclusion criteria
1. Subject is 12 months to \<24 months of age at screening. 2. Subject is intubated and mechanically ventilated in an intensive care setting and is anticipated to require a minimum of 6 hours of continuous IV sedation. 3. Subject has adequate renal function, defined as: Serum creatinine ≤1.0 mg/dL. 4. The subject's parent(s) or legal guardian(s) must voluntarily sign and date the informed consent document approved by the Institutional Review Board.
Exclusion criteria
1. Pediatric subjects with neurological conditions that prohibit an evaluation of sedation such as: * Diminished consciousness from increased intracranial pressure * Extensive brain surgery (surgery requiring intracranial pressure monitor) * Diminished cognitive function per Principal Investigator (PI) discretion * Subjects with immobility from neuromuscular disease or continuous infusion of neuromuscular blocking agents. 2. Subjects with second degree or third degree heart block unless subject has a permanent pacemaker or pacing wires are in situ. 3. 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. 4. 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. 5. Pre-existing bradycardia based on repeated assessments within 15 minutes preceding the start of study drug, defined as: Heart rate (HR) \<70 bpm. 6. Subject who have acute thermal burns involving more than 15 percent total body surface area. 7. Subjects who have a known allergy to dexmedetomidine, midazolam or fentanyl. 8. Subject who has received dexmedetomidine within 15 hours prior to the start of study drug. 9. Subjects with a life expectancy that is \<72 hours. 10. 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. 11. Subjects who have been treated with α-2 agonists/antagonists within 2 weeks. 12. Subjects with a spinal cord injury above T5 (5th Thoracic Vertebra). 13. Subjects who have received another investigational drug as part of an investigational drug study within the past 30 days. 14. Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of this clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve (AUC0-∞) | 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 | Area under the plasma concentration-time curve of dexmedetomidine at 0 to Infinity hours |
| Observed Peak Plasma Concentration (Cmax) | 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 | Maximum observed concentration of dexmedetomidine in plasma |
| Steady State Concentration (Css) | 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 | Concentration of dexmedetomidine at steady state in plasma |
| Terminal Elimination Half-life (t1/2) | 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 of dexmedetomidine. Half-life is the time required for plasma concentration of the drug to decrease by 50%. |
| Time to Reach Maximum Plasma Concentration (Tmax) | 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 time to reach maximum plasma concentration of dexmedetomidine, expressed in hours |
| Weight-Adjusted Plasma Clearance (CLw) | 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 Plasma Clearance of dexmedetomidine after intravenous administration. |
| Plasma Clearance (CL) | 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 | Clearance of dexmedetomidine after intravenous administration. Clearance is the rate at which the drug is removed from the plasma after the dose. |
| Volume of Distribution (Vd) | 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 of dexmedetomidine after intravenous administration. Volume of distribution measures how much the drug spreads through the body after the dose. |
| Weight-Adjusted Volume of Distribution (Vdw) | 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 of dexmedetomidine after intravenous administration. |
| Average Total Faces, Legs, Activity, Cry, and Consolability (FLACC) Score | 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 | 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. |
| Absolute Time That Subject is in UMSS Range 2-4 During Treatment Period | During the treatment (6 to 24 hours) | 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. |
| Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | During the treatment (6 to 24 hours) | Participants who received rescue medication midazolam for sedation and/or fentanyl for analgesic during study drug Infusion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Dexmedetomidine 0.7 mcg/kg loading dose and 0.5 mcg/kg/hr maintenance infusion | 2 |
| Dose Level 2 Dexmedetomidine 1.0 mcg/kg loading dose and 0.75 mcg/kg/hr maintenance infusion | 3 |
| Total | 5 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Total |
|---|---|---|---|
| Age, Continuous | 1.43 years STANDARD_DEVIATION 0.312 | 1.45 years STANDARD_DEVIATION 0.274 | 1.44 years STANDARD_DEVIATION 0.249 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 1 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 |
Outcome results
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.
Time frame: During the treatment (6 to 24 hours)
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Absolute Time That Subject is in UMSS Range 2-4 During Treatment Period | 3.6 Hours | Standard Deviation 3.48 |
| Dose Level 2 | Absolute Time That Subject is in UMSS Range 2-4 During Treatment Period | 5.8 Hours | Standard Deviation 0.38 |
Primary
Area Under the Plasma Concentration-time Curve (AUC0-∞)
Area under the plasma concentration-time curve of dexmedetomidine at 0 to Infinity hours
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Area Under the Plasma Concentration-time Curve (AUC0-∞) | 4639.17 picogram*hour per millilitre | Standard Deviation 4058.1893 |
| Dose Level 2 | Area Under the Plasma Concentration-time Curve (AUC0-∞) | 14203.544 picogram*hour per millilitre | Standard Deviation 13051.685 |
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.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Average Total Faces, Legs, Activity, Cry, and Consolability (FLACC) Score | 1.575 units on a scale | Standard Deviation 2.2274 |
| Dose Level 2 | Average Total Faces, Legs, Activity, Cry, and Consolability (FLACC) Score | 3.220 units on a scale | Standard Deviation 2.1707 |
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
Time frame: During the treatment (6 to 24 hours)
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate pharmacokinetic samples to estimate primary parameters.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 | Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Midazolam for sedation | 1 participants |
| Dose Level 1 | Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Fentanyl for Analgesic | 1 participants |
| Dose Level 2 | Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Midazolam for sedation | 1 participants |
| Dose Level 2 | Number of Subjects Who Received Rescue Medication for Sedation and Analgesic | Fentanyl for Analgesic | 2 participants |
Primary
Observed Peak Plasma Concentration (Cmax)
Maximum observed concentration of dexmedetomidine in plasma
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Observed Peak Plasma Concentration (Cmax) | 4499.925 picogram per millilitre | Standard Deviation 5826.7367 |
| Dose Level 2 | Observed Peak Plasma Concentration (Cmax) | 11737.387 picogram per millilitre | Standard Deviation 3549.7923 |
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.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Plasma Clearance (CL) | 12.192 Litre per Hour | Standard Deviation 9.577 |
| Dose Level 2 | Plasma Clearance (CL) | 5.836 Litre per Hour | Standard Deviation 2.9357 |
Primary
Steady State Concentration (Css)
Concentration of dexmedetomidine at steady state in plasma
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Steady State Concentration (Css) | 752.298 picogram per millilitre | Standard Deviation 658.0848 |
| Dose Level 2 | Steady State Concentration (Css) | 2303.277 picogram per millilitre | Standard Deviation 2116.4895 |
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%.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Terminal Elimination Half-life (t1/2) | 1.958 Hours | Standard Deviation 0.3765 |
| Dose Level 2 | Terminal Elimination Half-life (t1/2) | 2.260 Hours | Standard Deviation 1.2205 |
Primary
Time to Reach Maximum Plasma Concentration (Tmax)
Observed time to reach maximum plasma concentration of dexmedetomidine, expressed in hours
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Time to Reach Maximum Plasma Concentration (Tmax) | 0.083 Hours | Standard Deviation 0 |
| Dose Level 2 | Time to Reach Maximum Plasma Concentration (Tmax) | 0.283 Hours | Standard Deviation 0.3464 |
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.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Volume of Distribution (Vd) | 31.845 Litre | Standard Deviation 20.4351 |
| Dose Level 2 | Volume of Distribution (Vd) | 15.780 Litre | Standard Deviation 3.5461 |
Primary
Weight-Adjusted Plasma Clearance (CLw)
Weight-Adjusted Plasma Clearance of dexmedetomidine after intravenous administration.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Weight-Adjusted Plasma Clearance (CLw) | 1.292 Litre per Hours per Kilogram | Standard Deviation 1.13 |
| Dose Level 2 | Weight-Adjusted Plasma Clearance (CLw) | 0.617 Litre per Hours per Kilogram | Standard Deviation 0.3815 |
Primary
Weight-Adjusted Volume of Distribution (Vdw)
Weight-Adjusted Volume of distribution of dexmedetomidine after intravenous administration.
Time frame: 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
Population: Full Evaluable Population consisted of all subjects who received study drug for at least 5 hours with adequate PK samples to estimate primary parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Weight-Adjusted Volume of Distribution (Vdw) | 3.343 Litre per Kilogram | Standard Deviation 2.491 |
| Dose Level 2 | Weight-Adjusted Volume of Distribution (Vdw) | 1.590 Litre per Kilogram | Standard Deviation 0.6201 |