DOSE Trial of Opioid Sparing Effect

Mechanical Ventilation Complication Clinical Trial

— DOSE  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03938857
• Other study ID #: Pro00102267
• Secondary ID: 5U24TR001608
• Status: Terminated
• Phase: Phase 1
• Start date: July 18, 2019
• Est. completion date: November 6, 2020

Study information

• Verified date: October 2021
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 30
• Est. completion date: November 6, 2020
• Est. primary completion date: October 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Critical Illness
• Critically Ill
• Dexmedetomidine
• Mechanical Ventilation Complication

Intervention

Drug:
• Fentanyl
Fentanyl standard of care
• Dexmedetomidine
Dexmedetomidine (0.5 mcg/kg + 0.2 mcg/kg/hr)
• Dexmedetomidine
Dexmedetomidine (0.5 mcg/kg + 0.5 mcg/kg/hr)
• Dexmedetomidine
Dexmedetomidine (0.5 mcg/kg + 0.7 mcg/kg/hr)

Locations

Country	Name	City	State
United States	University of New Mexico Children's Hospital	Albuquerque	New Mexico
United States	Our Lady of the Lake Children's Hospital	Baton Rouge	Louisiana
United States	University of Buffalo, Oishei Children's Hospital	Buffalo	New York
United States	Medical University of South Carolina Children's Hospital	Charleston	South Carolina
United States	MetroHealth System, Case CTSA	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital, University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida, Shands Children's Hospital	Gainesville	Florida
United States	Indiana University Health, Riley Hospital for Children	Indianapolis	Indiana
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Minnesota Masonic Children's Hospital	Minneapolis	Minnesota
United States	Drexel University, St. Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Oregon Health and Science University, Doernbecher Children's Hospital	Portland	Oregon
United States	University of Rochester Medical Center, Golisano Children's Hospital	Rochester	New York
United States	Saint Louis University, Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Primary Children's Medical Center- University of Utah	Salt Lake City	Utah
United States	University of Texas - Health Science Center San Antonio	San Antonio	Texas
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina
United States	UMass Memorial Medical Center, Children's Center	Worcester	Massachusetts

Sponsors (5)

Lead Sponsor	Collaborator
Duke University	Intermountain Health Care, Inc., Johns Hopkins University, National Institutes of Health (NIH), Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Average Daily Cornell Assessment of Pediatrics in Delirium (CAPD) Scores	Estimate the incidence of intensive care unit delirium in children exposed to fentanyl and dexmedetomidine alone or in combination when receiving mechanical ventilation. (Measures of delirium). The CAPD scale goes from 0-4 and has 8 questions. All items scored as occurring never, rarely, sometimes, often, or always. Individual item scores are added for a sum total score.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Other	Maximum Daily CAPD Scores	Estimate the incidence of intensive care unit delirium in children exposed to fentanyl and dexmedetomidine alone or in combination when receiving mechanical ventilation. (Measures of delirium). The CAPD scale goes from 0-4 and has 8 questions. All items scored as occurring never, rarely, sometimes, often, or always. Individual item scores are added for a sum total score.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Other	Minimum Daily CAPD Scores	Estimate the incidence of intensive care unit delirium in children exposed to fentanyl and dexmedetomidine alone or in combination when receiving mechanical ventilation. (Measures of delirium). The CAPD scale goes from 0-4 and has 8 questions. All items scored as occurring never, rarely, sometimes, often, or always. Individual item scores are added for a sum total score.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Other	Average Daily Withdrawal Assessment Tool (WAT-1) Score	Estimate the incidence of opioid withdrawal syndrome in children exposed to fentanyl and dexmedetomidine when administered alone or in combination when receiving mechanical ventilation. (Measures of withdrawal). WAT-1 scale is 0=no/none and 1=yes/moderate/severe. Total score is on a 0-12 scale where lower is better.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Other	Minimum Daily WAT-1 Score	Estimate the incidence of opioid withdrawal syndrome in children exposed to fentanyl and dexmedetomidine when administered alone or in combination when receiving mechanical ventilation. (Measures of withdrawal). WAT-1 scale is 0=no/none and 1=yes/moderate/severe. Total score is on a 0-12 scale where lower is better.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Other	Maximum Daily WAT-1 Score	Estimate the incidence of opioid withdrawal syndrome in children exposed to fentanyl and dexmedetomidine when administered alone or in combination when receiving mechanical ventilation. (Measures of withdrawal). WAT-1 scale is 0=no/none and 1=yes/moderate/severe. Total score is on a 0-12 scale where lower is better.	through day 7 of mechanical ventilation or initial extubation (whichever is first)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Number of Participants Experiencing SAEs (Serious Adverse Events)		up to 28 days or until discharge from the ICU (whichever is first)
Secondary	Mean Number of SAEs (Serious Adverse Events) Experienced by Participants		up to 28 days or until discharge from the ICU (whichever is first)
Secondary	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)
Secondary	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)