Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial) (DICE)

Management of neonatal pain and sedation often includes opioid therapy. A growing body of evidence suggests long-term harm associated with neonatal opioid exposure. Providing optimal sedation while neonates are undergoing therapeutic hypothermia (TH) may be beneficial but also presents therapeutic challenges. While there is evidence from animal models of brain injury and clinical trials in adults to support the safety and neuroprotective properties of dexmedetomidine (DMT), there are no published large clinical trials demonstrating safety and efficacy of DMT use in neonates with hypoxic-ischemic encephalopathy (HIE) during treatment with TH. This study is innovative in proposing a Phase II, 2-arm trial providing the opportunity to evaluate the use of DMT as compared to the use of morphine for sedation and pain management for babies undergoing TH. We propose to confirm optimal DMT dosing by collecting opportunistic pharmacokinetics (PK) data and determine safety of DMT in this population. These data will inform a larger phase III efficacy trial.

Study Overview

• Status: Recruiting
• Conditions: Pain; Hypoxic-Ischemic Encephalopathy
• Intervention / Treatment: Drug: Dexmedetomidine Hydrochloride; Drug: Morphine Sulfate

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
• Study Contact Backup: Name: Carrie Rau, RN; Phone Number: 801-213-3360; Email: carrie.rau@hsc.utah.edu

Study Locations

• United States
  • Utah
    • Murray, Utah, United States, 84107
      • Recruiting
      • Intermountain Medical Center
      • Contact: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
      • Contact: Kimberlee Weaver-Lewis, RN, MS; Phone Number: 801-507-7675; Email: kimberlee.weaverlewis@imail.org
    • Ogden, Utah, United States, 84403
      • Recruiting
      • McKay-Dee Hospital
      • Contact: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
      • Contact: Kimberlee Weaver-Lewis, RN, MS; Phone Number: 801-507-7675; Email: kimberlee.weaverlewis@imail.org
    • Provo, Utah, United States, 84604
      • Recruiting
      • Utah Valley Hospital
      • Contact: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
      • Contact: Kimberlee Weaver-Lewis, RN, MS; Phone Number: 801-507-7675; Email: kimberlee.weaverlewis@imail.org
    • Salt Lake City, Utah, United States, 84113
      • Recruiting
      • Primary Children's Hospital
      • Contact: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
      • Contact: Kimberlee Weaver-Lewis, RN; Phone Number: 801-507-7675; Email: kimberlee.weaverlewis@imail.org
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah Health
      • Contact: Mariana Baserga, MD; Phone Number: 801-581-4178; Email: mariana.baserga@hsc.utah.edu
      • Contact: Carrie Rau, RN; Phone Number: 801-213-3360; Email: carrie.rau@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe neonatal encephalopathy and treated with TH (target temperature 33.5°C) for a planned duration of 72 h.
• Infants requiring sedation and/or treatment to prevent shivering during TH as assessed by the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) scores and a modified Bedside Shivering Assessment Scale.
• Informed consent document approved by the Institutional Review Board (IRB) obtained prior to randomization

Exclusion Criteria:

• Known chromosomal anomalies
• Cyanotic congenital heart defects
• Redirection of care being considered because of moribund condition, or a decision made to withhold full support

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine (DMT); Subjects randomized to DMT arm in a 1:1 ratio. A loading dose of 1 mcg/kg will be given followed by 0.1 to 0.5 mcg/kg/h continuous infusion. The Neonatal Pain, Agitation, and Sedation Scale (N-PASS) will be used to determine infusion rate.	Drug: Dexmedetomidine Hydrochloride; Potent α2-adrenergic receptor agonist that provides sedation, analgesia, and prevents shivering but does not suppress ventilation.
Active Comparator: Morphine; Subjects randomized to morphine in a 1:1 ratio. Intermittent dosing every 3-4 hours of 0.02-0.05 mg/kg/dose or continuous infusion of 0.005 to 0.01 mg/kg/hr. The N-PASS will be used to determine dosing and frequency.	Drug: Morphine Sulfate; Opioid agonist that provides analgesia, pain management and sedation and may suppress ventilation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Examine Safety Measures in infants receiving DMT to those receiving morphine	Safety will be evaluated during the first 4 days of life by documenting potential adverse events such hypotension, hypertension, bradycardia, cardiac arrhythmias, hypothermia, acute renal failure, liver failure, and seizures outside of normal range for the study population.	First 96 hours of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DMT plasma levels	Two opportunistic PK samples (at time of routine laboratories) and a PK sample any time there is an adverse event will be obtained for measurement of DMT plasma concentrations as needed.	one week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants who experience shivering	Number of babies who experience shivering during therapeutic hypothermia will be compared between the two drug treatment regimens	First 96 hours of life
Number of participants who require respiratory support	Number of babies who require respiratory support will be compared between the two drug treatment regimens. This will include ventilator, continuous positive airway pressure, and oxygen use	First week of life
Days to full oral feedings by bottle or breast	Days to full oral feedings will be compared between the two drug treatment regimens	Up to two months
Generalized Motor Assessment Scores (GMA) 7 days after weaned off of study drug or discharge, whichever happens first	the GMA is a validated test that aids in early detection of neurological movement disorders by evaluating the quality of movements during a 2-minute video. Certified assessors will grade the quality of movements which include: normal writhing, poor repertoire, cramped synchronized, and chaotic movements. All movements other than normal writhing are considered atypical. The results will be compared between the two drug treatments.	up to 3 weeks
Generalized Motor Assessment Scores at 3-4 months of age	the GMA is a validated test that aids in early detection of neurological movement disorders by evaluating the quality of movements during a 2-minute video. Certified assessors will grade the quality of movements which include: normal writhing, poor repertoire, cramped synchronized, and chaotic movements. All movements other than normal writhing are considered atypical. The results will be compared between the two drug treatments.	3-4 months of age
Hammersmith Infant Neurological Exam (HINE) scores at 3-4 months of age	The HINE is a 26 item exam that assesses different aspects of neurological function and these scores will be compared between the two drug treatment regimens. This assessment scores 5 different neurological development areas: Cranial nerve function, posture, movements, tone, and reflexes/reactions. The maximum score is 78 and lowest score is 0. Higher scores show better neurological development consistent with better outcomes.	3-4 months of age
Hammersmith Infant Neurological Exam (HINE) scores at 6-9 months of age	The HINE is a 26 item exam that assesses different aspects of neurological function and these scores will be compared between the two drug treatment regimens. This assessment scores 5 different neurological development areas: Cranial nerve function, posture, movements, tone, and reflexes/reactions. The maximum score is 78 and lowest score is 0. Higher scores show better neurological development consistent with better outcomes.	6-9 months of age
Test of Infant Motor Performance (TIMP) scores at 3-4 months of corrected age	This test evaluates posture and motor control and is designed to be used specifically in infants born prematurely. Results are given based on z-scores from normative values and are given as low average, below average, and far below average. Lower scores are more predictive of worse outcomes. These scores will be compared between the two drug treatment regimens.	3-4 months of corrected age
Peabody Developmental Motor Skills (PDMS-2) at 6-9 months of age	This test evaluates fine motor, gross motor, and total motor skills. Results are converted to age equivalent rating and then quotient scores are given for each category. Minimum is 35 and maximum is 165. The average score is 90-110, with higher scores given in 3 SD above average performance and lower scores given in 3 SD below average performance.The higher the score, the better predicted outcome. These scores will be compared between the two drug treatment regimens.	6-9 months of age
Ages and Stages Questionnaire at 6-9 months of age	Parental survey that assesses communication, gross and fine motor skills, and social behaviors. Scores range from 0-60, and the higher the score, the better the outcome. These scores will be compared between the two drug treatment regimens	6-9 months of age

Collaborators and Investigators

• Sponsor: University of Utah
• Investigators: Principal Investigator: Mariana Baserga, MD, University of Utah

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2022
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: February 18, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 26, 2021

Study Record Updates

• Last Update Posted (Actual): July 21, 2023
• Last Update Submitted That Met QC Criteria: July 19, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Therapeutic hypothermia; dexmedetomidine
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Diseases; Hypoxia-Ischemia, Brain; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Dexmedetomidine; Morphine
• Other Study ID Numbers: 136561

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No