Clinical trial NCT03938857: DOSE Trial of Opioid Sparing Effect
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Dexmedetomidine
Mechanical Ventilation Complication
Critically Ill
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Johns Hopkins University
name: Intermountain Health Care, Inc.
name: Vanderbilt University Medical Center
First posted: 2019-05-06
Enrollment: 30
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Ages 0 to \<18 years at the time of enrollment.
2. If \< 6 months postnatal age, gestational age ≥ 35 weeks.
3. Admitted to an intensive care unit.
4. Planned or anticipated mechanically ventilation for ≥2 days.
5. Require sedation to maintain mechanical ventilation per clinical judgment.
6. No contraindication to receipt of fentanyl or dexmedetomidine per clinician judgment.
7. Availability and willingness of the parent/legal guardian to provide written informed consent.

Exclusion Criteria:

1. Previous participation in this study.
2. Severe traumatic brain injury as the underlying etiology for critical illness requiring mechanical ventilation or baseline pediatric cerebral performance category (PCPC) \>3.
3. Planned receipt of sedatives other than fentanyl or dexmedetomidine.
4. Anticipated receipt of neuromuscular blockade for \>48 consecutive hours during the study period.
5. Receipt of fentanyl or dexmedetomidine via continuous infusion for \>12 hours in the 24 hours prior to enrollment.
6. Extracorporeal life support (including renal replacement therapy, extracorporeal membrane oxygenation, ventricular assist device, etc.) at the time of enrollment.
7. 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)
8. Known pregnancy
9. Known liver dysfunction, defined as: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2x the upper limit of normal for age
10. Known or impending renal failure defined as: anuria \> or equal to 12 hours prior to enrollment or requiring renal replacement therapy
11. 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)
12. 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.

Primary outcomes:
measure: Mean Daily Dose of Fentanyl in mcg/kg/hr (Micrograms Per Kilogram Per Hour)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Secondary outcomes:
measure: Sedation Based on the State Behavior Scale (SBS) Relative to Fentanyl Plasma Concentrations (Cmax)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Cmin)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Css)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (AUC)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Css)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on Richmond Agitation and Sedation Scale (RASS) Scale Relative to Fentanyl Plasma Concentrations (Cmax)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Cmin)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Css)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (AUC)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Css)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC)
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Number of Participants Experiencing a Clinically Significant Episode of Hypotension
timeFrame: up to 28 days or until discharge from the ICU (whichever is first)
measure: Number of Participants Experiencing SAEs (Serious Adverse Events)
timeFrame: up to 28 days or until discharge from the ICU (whichever is first)
measure: Mean Number of SAEs (Serious Adverse Events) Experienced by Participants
timeFrame: up to 28 days or until discharge from the ICU (whichever is first)
measure: Number of Participants Experiencing a Clinically Significant Episode of Bradycardia
timeFrame: up to 28 days or until discharge from the ICU (whichever is first)
measure: Number of Participants Experiencing a Clinically Significant Episode of Urinary Retention
timeFrame: up to 28 days or until discharge from the ICU (whichever is first)
Other outcomes:
measure: Average Daily Cornell Assessment of Pediatrics in Delirium (CAPD) Scores
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Maximum Daily CAPD Scores
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Minimum Daily CAPD Scores
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Average Daily Withdrawal Assessment Tool (WAT-1) Score
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Minimum Daily WAT-1 Score
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
measure: Maximum Daily WAT-1 Score
timeFrame: through day 7 of mechanical ventilation or initial extubation (whichever is first)
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Gainesville
country: United States
facility: University of Florida, Shands Children's Hospital
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Health, Riley Hospital for Children
state: Indiana
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Children's Hospital
state: Louisiana
city: Worcester
country: United States
facility: UMass Memorial Medical Center, Children's Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Children's Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University, Cardinal Glennon Children's Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico Children's Hospital
state: New Mexico
city: Buffalo
country: United States
facility: University of Buffalo, Oishei Children's Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center, Golisano Children's Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital, University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth System, Case CTSA
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University, Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University, St. Christopher's Hospital for Children
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina Children's Hospital
state: South Carolina
city: San Antonio
country: United States
facility: University of Texas - Health Science Center San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center- University of Utah
state: Utah
Study officials:
affiliation: Duke Clinical Research Institute
name: Daniel Benjamin, MD
role: PRINCIPAL_INVESTIGATOR
References: