DOSE Trial of Opioid Sparing Effect

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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DEXMEDETOMIDINE OPIOID SPARING EFFECT IN MECHANICALLY VENTILATED CHILDREN: Phase 1b, Multicenter, Double Blind Randomized Controlled Dose Escalating Trial of Fentanyl vs. Fentanyl + Dexmedetomidine as the Initial Regimen for Maintenance of Sedation in Mechanically-ventilated, Critically Ill Children

Conditions
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Dexmedetomidine, Mechanical Ventilation Complication, Critically Ill

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Dexmedetomidine
* Drug: Dexmedetomidine
* Drug: Dexmedetomidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 0 to <18 years at the time of enrollment. If < 6 months postnatal age, gestational age ≥ 35 weeks. Admitted to an intensive care unit. Planned or anticipated mechanically ventilation for ≥2 days. Require sedation to maintain mechanical ventilation per clinical judgment. No contraindication to receipt of fentanyl or dexmedetomidine per clinician judgment. Availability and willingness of the parent/legal guardian to provide written informed consent. Exclusion Criteria: Previous participation in this study. Severe traumatic brain injury as the underlying etiology for critical illness requiring mechanical ventilation or baseline pediatric cerebral performance category (PCPC) >3. Planned receipt of sedatives other than fentanyl or dexmedetomidine. Anticipated receipt of neuromuscular blockade for >48 consecutive hours during the study period. Receipt of fentanyl or dexmedetomidine via continuous infusion for >12 hours in the 24 hours prior to enrollment. Extracorporeal life support (including renal replacement therapy, extracorporeal membrane oxygenation, ventricular assist device, etc.) at the time of enrollment. Chronic use of or recent overdose of serotonergic agents (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase (MAO) inhibitors, cyclic antidepressants) Known pregnancy Known liver dysfunction, defined as: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2x the upper limit of normal for age Known or impending renal failure defined as: anuria > or equal to 12 hours prior to enrollment or requiring renal replacement therapy High risk children, define as: a. known heart block b. known bradyarrythmia including clinically significant bradycardia (defined as requiring chronotropic agents or cardiac pacing to treat) Receipt of mechanical ventilation during an admission for cardiac surgery Note: receipt of drugs other than fentanyl or dexmedetomidine for intubation, and receipt of neuromuscular blockage for intubation, will not be considered exclusionary criteria.

Ages Eligible for Study
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Maximum Age: 18 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1b randomized, double-blind, placebo-controlled dose escalation trial. 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); Cohort 3: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Fen. SOC+saline placebo (bolus+infusion)<br>Fentanyl standard of care (SOC) titrated to sedation + saline placebo (bolus + infusion) | Drug: Fentanyl<br>* Fentanyl standard of care<br>|
| Active Comparator: Fen. SOC+Dex.(.5mcg/kg + .25mcg/kg/hr)<br>Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.2mcg/kg/hr infusion) | Drug: Fentanyl<br>* Fentanyl standard of care<br>Drug: Dexmedetomidine<br>* Dexmedetomidine (0.5 mcg/kg + 0.2 mcg/kg/hr)<br>|
| Active Comparator: Fen. SOC+Dex.(.5mcg/kg + .5mcg/kg/hr)<br>Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.5mcg/kg/hr infusion) | Drug: Fentanyl<br>* Fentanyl standard of care<br>Drug: Dexmedetomidine<br>* Dexmedetomidine (0.5 mcg/kg + 0.5 mcg/kg/hr)<br>|
| Active Comparator: Fen. SOC+Dex.(.5mcg/kg + .75mcg/kg/hr)<br>Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion) | Drug: Fentanyl<br>* Fentanyl standard of care<br>Drug: Dexmedetomidine<br>* Dexmedetomidine (0.5 mcg/kg + 0.7 mcg/kg/hr)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | through day 7 of mechanical ventilation or initial extubation (whichever is first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | up to 28 days or until discharge from the ICU (whichever is first) | 
| Number of Participants Experiencing SAEs (Serious Adverse Events) |  | up to 28 days or until discharge from the ICU (whichever is first) | 
| Mean Number of SAEs (Serious Adverse Events) Experienced by Participants |  | 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. | 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. | up to 28 days or until discharge from the ICU (whichever is first) |