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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexmedetomidine (DMT) | Experimental | 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. |
|
| Morphine | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine Hydrochloride | Drug | Potent α2-adrenergic receptor agonist that provides sedation, analgesia, and prevents shivering but does not suppress ventilation. |
|
| 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 comparing number of serious adverse events between two study arms. | First 96 hours of life |
| 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. Because these PK samples are done opportunistically, there are no pre-set defined time points for PK measurements. | one week |
| 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 Days Intubated |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mariana Baserga, MD | University of Utah | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Intermountain Medical Center | Murray | Utah | 84107 | United States | ||
| McKay-Dee Hospital |
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The intent of the protocol was to replace any babies who were deemed not evaluable (didn't receive study drug) with another enrollment to have a total of 50 evaluable subjects enrolled.
Enrolled from June 2022 to Jan 2025 and a total of 50 babies were consented to the study. Two babies were withdrawn due to no receipt of study drug, making enrollment of evaluable babies a total of 48.Due to slow enrollment and lack of funding, enrollment of evaluable babies completed at 48 instead of 50.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Dexmedetomidine Hydrochloride: Potent α2-adrenergic receptor agonist that provides sedation, analgesia, and prevents shivering but does not suppress ventilation. |
| FG001 | 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. Morphine Sulfate: Opioid agonist that provides analgesia, pain management and sedation and may suppress ventilation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Babies >/= to 36 weeks gestation diagnosed with hypoxic-ischemic encephalopathy and receiving therapeutic hypothermia per NICU standard care
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Dexmedetomidine Hydrochloride: Potent α2-adrenergic receptor agonist that provides sedation, analgesia, and prevents shivering but does not suppress ventilation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Examine Safety Measures in Infants Receiving DMT to Those Receiving Morphine | Safety will be evaluated during the first 4 days of life by comparing number of serious adverse events between two study arms. | Posted | Number | Number of serious adverse events | First 96 hours of life |
|
Adverse events were reported that occured from randomization to 96 hours of life (study interventions phase). Serious adverse events were recorded if they occurred from randomization to 7 days post last study drug dose or hospital discharge up to 11 days, whichever occurred first.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Multi-organ failure | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bradycardia | Cardiac disorders | Systematic Assessment | Decrease in baseline heart rate of at least 10 beats per minute OR \ |
A limitation of the DICE trial design was that it was unblinded. This was due to morphine given as an intermittent bolus dose in our NICUs whereas dexmedetomidine can only be given continuous. Another important limitation was the number of protocol deviations, mostly related to N-PASS scores measured at the wrong times or drug dose adjustments not documented. This issue was as frequent in both arms of the trial but could have affected some of the results.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mariana Baserga, PI | University of Utah | 310-401-5643 | mariana.baserga@hsc.utah.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 8, 2024 | Jan 6, 2026 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D020925 | Hypoxia-Ischemia, Brain |
| D010146 | Pain |
| ID | Term |
|---|---|
| D002545 | Brain Ischemia |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D009020 | Morphine |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Infants randomized to receive open-label dexmedetomidine (DMT) or morphine for pain and sedation.
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| Morphine Sulfate | Drug | Opioid agonist that provides analgesia, pain management and sedation and may suppress ventilation. |
|
Number of days each subject required invasive ventilator support will be compared between arms.
| 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 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 |
| Ogden |
| Utah |
| 84403 |
| United States |
| Utah Valley Hospital | Provo | Utah | 84604 | United States |
| Primary Children's Hospital | Salt Lake City | Utah | 84113 | United States |
| University of Utah Health | Salt Lake City | Utah | 84132 | United States |
| BG001 | 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. Morphine Sulfate: Opioid agonist that provides analgesia, pain management and sedation and may suppress ventilation. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | 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. Because these PK samples are done opportunistically, there are no pre-set defined time points for PK measurements. | Pharmacokinetics were only analyzed in the dexmedetomidine group. | Posted | Median | Full Range | Dexemedetomidine concentration in pg/mL | one week |
|
|
|
| Other Pre-specified | Number of Participants Who Experience Shivering | Number of babies who experience shivering during therapeutic hypothermia will be compared between the two drug treatment regimens | Posted | Count of Participants | Participants | First 96 hours of life |
|
|
|
| Other Pre-specified | Number of Days Intubated | Number of days each subject required invasive ventilator support will be compared between arms. | Posted | Median | Inter-Quartile Range | Number of days intubated | First week of life |
|
|
|
| Other Pre-specified | Days to Full Oral Feedings by Bottle or Breast | Days to full oral feedings will be compared between the two drug treatment regimens | Posted | Median | Inter-Quartile Range | Number of days to full feeds | Up to two months |
|
|
|
| Other Pre-specified | 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. | Not Posted | Dec 2026 | 3-4 months of age | Participants |
| Other Pre-specified | 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. | Not Posted | Dec 2026 | 3-4 months of age | Participants |
| Other Pre-specified | 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. | Not Posted | Dec 2026 | 6-9 months of age | Participants |
| Other Pre-specified | 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. | Not Posted | Dec 2026 | 3-4 months of corrected age | Participants |
| Other Pre-specified | 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. | Not Posted | Dec 2026 | 6-9 months of age | Participants |
| Other Pre-specified | 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 | Not Posted | Dec 2026 | 6-9 months of age | Participants |
| 0 |
| 25 |
| 1 |
| 25 |
| 16 |
| 25 |
| EG001 | 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. | 1 | 23 | 1 | 23 | 8 | 23 |
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Respiratory failure requiring intubation after randomization |
|
|
| Tachycardia | Cardiac disorders | Systematic Assessment | Heart rate > 200 beats per minute |
|
| Hypotension | Cardiac disorders | Systematic Assessment | A decrease in mean blood pressure that required intervention |
|
| Hypertension | Cardiac disorders | Systematic Assessment | Mean arterial pressure > 90th percentile |
|
| Seizures | Nervous system disorders | Systematic Assessment | New onset confirmed EEG seizures |
|
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| D009422 | Nervous System Diseases |
| D002534 | Hypoxia, Brain |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000860 | Hypoxia |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009461 | Neurologic Manifestations |
| D009022 |
| Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |