Multicenter, double blind randomized controlled trial of fentanyl vs. fentanyl + dexmedetomidine as the initial regimen for maintenance of sedation in mechanically-ventilated, critically ill children. This trial will evaluate the opioid-sparing effect of dexmedetomidine when administered with fentanyl to mechanically ventilated, critically ill children. Study drug or placebo will be administered with fentanyl, which will be titrated to achieve sedation scores consistent with response to light touch. Plasma samples and bedside assessments for pain, sedation, and delirium will be collected.
Phase 1b randomized, double-blind, placebo-controlled dose escalation trial of sedation regimens in critically ill children. Testing the hypothesis of mean daily fentanyl dose through day 7 of mechanical ventilation will be reduced by ≥25% by the addition of dexmedetomidine to fentanyl therapy. This trial will involve multiple clinical sites. Randomization will occur by individual and investigators will be blinded to study/treatment arm. The statistical analysis will account for center effects, participant characteristics (including post-surgical state), and changes over time to minimize bias. In addition, PIs and study coordinators will undergo training to standardize assessment procedures. The study will randomize participants to receive placebo (fentanyl standard of care) titrated to sedation+saline placebo (bolus+infusion) or one of the following 3 Dexmedetomidine treatment arms in a sequential cohort fashion: Cohort 1: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.2 mcg/kg/hr infusion); Cohort 2: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.5mcg/kg/hr infusion); and, Cohort 3: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion). An interim analysis is planned for this trial.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
30
Fentanyl standard of care
Dexmedetomidine (0.5 mcg/kg + 0.2 mcg/kg/hr)
Dexmedetomidine (0.5 mcg/kg + 0.5 mcg/kg/hr)
Dexmedetomidine (0.5 mcg/kg + 0.7 mcg/kg/hr)
Arkansas Children's Hospital
Little Rock, Arkansas, United States
University of Florida, Shands Children's Hospital
Gainesville, Florida, United States
Indiana University Health, Riley Hospital for Children
Indianapolis, Indiana, United States
Our Lady of the Lake Children's Hospital
Baton Rouge, Louisiana, United States
UMass Memorial Medical Center, Children's Center
Worcester, Massachusetts, United States
University of Minnesota Masonic Children's Hospital
Minneapolis, Minnesota, United States
Saint Louis University, Cardinal Glennon Children's Hospital
St Louis, Missouri, United States
University of New Mexico Children's Hospital
Albuquerque, New Mexico, United States
University of Buffalo, Oishei Children's Hospital
Buffalo, New York, United States
University of Rochester Medical Center, Golisano Children's Hospital
Rochester, New York, United States
...and 9 more locations
Mean Daily Dose of Fentanyl in mcg/kg/hr (Micrograms Per Kilogram Per Hour)
Characterize the opioid-sparing effect of dexmedetomidine when co-administered with fentanyl in children receiving mechanical ventilation. Characterization of differences between dosing exposures for the four groups will allow estimation of the opioid-sparing effect of dexmedetomidine.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on the State Behavior Scale (SBS) Relative to Fentanyl Plasma Concentrations (Cmax)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Cmin)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Css)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (AUC)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Css)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on Richmond Agitation and Sedation Scale (RASS) Scale Relative to Fentanyl Plasma Concentrations (Cmax)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Cmin)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-pint scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Css)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (AUC)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Css)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC)
Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Time frame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Number of Participants Experiencing a Clinically Significant Episode of Hypotension
Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Time frame: up to 28 days or until discharge from the ICU (whichever is first)
Number of Participants Experiencing SAEs (Serious Adverse Events)
Time frame: up to 28 days or until discharge from the ICU (whichever is first)
Mean Number of SAEs (Serious Adverse Events) Experienced by Participants
Time frame: up to 28 days or until discharge from the ICU (whichever is first)
Number of Participants Experiencing a Clinically Significant Episode of Bradycardia
Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Time frame: up to 28 days or until discharge from the ICU (whichever is first)
Number of Participants Experiencing a Clinically Significant Episode of Urinary Retention
Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Time frame: up to 28 days or until discharge from the ICU (whichever is first)
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