Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial)
Phase: PHASE2
Conditions: Hypoxic-Ischemic Encephalopathy, Pain
Sponsor: University of Utah

 
 
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Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal 
Encephalopathy (DICE trial) 
 
Protocol Version 6.0:  2/8/2024 
Sponsor:  NICHD 
Principal Investigator: Mariana Baserga, MD 
Internal Staff and Sub-Investigators:   
Tara DuPont, MD 
 
 
 
 
 
 
 
Kevin Watt, MD 
 
 
 
 
 
 
 
Betsy Ostrander 
 
 
 
 
 
 
 
Tim Bahr, MD 
 
 
 
 
 
 
 
Alfred Balch, MD 
External Sub-Investigators 
Stephen Minton, MD-Utah Valley Hospital (UVH) 
 
 
 
 
 
Erick Gerday, MD-Utah Valley Hospital (UVH) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Background and Introduction 
 
Neonatal encephalopathy (NE) due hypoxia-ischemia encephalopathy (HIE) remains 
the leading cause of neonatal mortality and long term poor neurodevelopmental 
outcomes worldwide (1-3). The incidence of HIE ranges from 1 to 7 per 1000 births, 
with most estimates ranging between 1 to 3 per 1000. Up to 12,000 infants are 
affected each year in the US (2). Therapeutic Hypothermia (TH) initiated within 6 
hours of life has become standard of care in developed countries and has been shown 
to mitigate brain damage (4-6). However, current data from the more recent cooling 
trials demonstrate that up to 30% of treated infants either died or had moderate to 
severe neurologic disabilities including long-term motor and cognitive dysfunction (7). 
Disabilities include cerebral palsy, mental retardation, epilepsy, and visual impairment 
among others adverse outcomes. No additional therapies have yet proven to be 
efficacious in further reducing brain injury and impairment for these high-risk infants.  
Newborns with moderate-to-severe NE may also present with multiorgan failure and 
may develop cardiovascular instability, renal and liver insufficiency, seizures, and 
respiratory failure requiring mechanical ventilation. Due to their critical condition in the 
Neonatal Intensive Care Unit (NICU) they commonly receive drugs such as morphine 
for pain and sedation management and to prevent shivering (8, 9). A recent study 
showed that up to 64% neonates treated with TH at 125 NICUs received opioids (10). 
However, the efficacy of morphine for sedation during TH has not been evaluated in 
clinical trials and has raised concerns for short and long-term safety issues including 
depressed ventilation, hypotension, gastrointestinal dysmotility and importantly, 
possible adverse effects on neurodevelopmental outcomes (11-13). For instance, 
morphine has been shown to increase apoptosis in both human microglial cells and 
neuronal like cells of neonatal rats (14-16). Furthermore, animal studies support long-
term negative effects on behavior and brain function following the administration of 
morphine to neonatal rats. Pups that received morphine from day 1-7 of life were 
smaller than saline-treated littermates and showed retarded motor development. As 
adults, the morphine-treated rats had impaired motor coordination, altered gait, and 
altered patterns of activity in an open field (17).  
In summary, there is insufficient evidence to recommend routine use of morphine 
during TH. Further research into the treatment of pain and stress during TH and its 
effects on the injured brain is essential to guide the development of clinical 
treatment protocols. 
Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better 
alternative to morphine for newborns with neonatal encephalopathy treated with TH 
(18). dexmedetomidine provides sedation, analgesia, and prevents shivering but 
does not suppress ventilation (19, 20). Importantly, there is increasing evidence that 
dexmedetomidine has neuroprotective properties in several injury models including 
ischemia-reperfusion, inflammation, anesthesia, and traumatic brain injury (21-25). 
In other preclinical studies of HIE insult, dexmedetomidine was shown to act as 
potent neuroprotector via stimulation of the α-2A adrenoreceptors (26). Exposure to 
dexmedetomidine following perinatal HIE reduced cortical and white matter lesion 
sizes and was associated with improved neurologic functional deficit (27).  

 
 
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Even though there are limited data on pharmacokinetics (PK), safety and efficacy of 
dexmedetomidine in infants with neonatal encephalopathy it has been increasingly 
administered in many centers (28-30).  
A recent phase I, single-center, open-label study evaluated the PK and safety of 
dexmedetomidine administered to 7 neonates ≥36 weeks gestational age with 
moderate-to-severe HIE, who received a continuous dexmedetomidine infusion 
during TH and during the 6 h rewarming period. In cooled newborns with HIE, 
dexmedetomidine clearance was either comparable or lower, distribution volume was 
larger, and elimination half-life was longer compared to corresponding values 
reported for normothermic newborns without HIE. No acute adverse events were 
associated with dexmedetomidine treatment in this small group of infants (18).  
Rationale and Justification 
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 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, there are no published large clinical trials 
demonstrating safety and efficacy of dexmedetomidine use in neonates with HIE 
during treatment with TH.  
This study is innovative in proposing a Phase II, 2-arm trial providing the 
opportunity to evaluate the use dexmedetomidine as compared to the use of 
morphine for sedation and pain management.  We propose to confirm optimal 
dexmedetomidine dosing by collecting opportunistic PK data and determine safety of 
dexmedetomidine in this population. These data will inform a larger phase III 
efficacy trial. 
The proposed study is also innovative in implementing the use of a battery of tests 
that have been shown to aid in the early detection of cerebral palsy (CP). These 
validated tests include the Generalized Movement Assessment (GMA) performed 1 
week (±2 days) after last dose of morphine or dexmedetomidine is given even if 
beyond treatment period is weaned off or around discharge, whichever happens first 
and at 3-4 months (±1 month) of life complemented with the Hammersmith Infant 
Neurological Exam (HINE) performed at 3-4 months (±1 month) and at 6-9 months 
(±1 month) of age. Additional testing to assess motor function includes the Test of 
Infant Motor Performance (TIMP) performed at 3-4 months (±1 month) and Peabody 
Developmental Motor Skills (PDMS-2) performed at 6-9 months (±1 month). The 
Ages and Stages Questionnaires (ASQ-3) will also be completed by parents at the 6–
9-month visit (±1 month) to screen infant in areas of communication, gross motor, 
fine motor, problem solving, and personal-social. 
Potential Impact 
Neonatal encephalopathy remains an important cause of death and adverse 
neurological outcome. TH has been shown to provide only partial 
neurodevelopmental benefit in these neonates. Because of the vulnerability of the 
brain following hypoxia ischemia, avoiding the use of potentially harmful drugs for 

 
 
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sedation such as morphine and replacing it with a potentially safer drug such as 
dexmedetomidine may further reduce brain injury. In the present study, we 
anticipate that dexmedetomidine administered for sedation during TH will be safe. In 
addition, we will further ascertain dexmedetomidine PK characteristics in these 
critically ill infants. Finally, we propose that the use of dexmedetomidine in this 
group of patients will demonstrate improved short and long-term outcomes. If we 
establish that dexmedetomidine administration during TH in neonates with 
encephalopathy is safe and is associated with improved outcomes, we plan 
to design a Phase III research proposal using the PK data obtained from 
this trial to further determine efficacy of this intervention on long-term 
neurodevelopment at 2 years of age.  
 
Supportive Preliminary Data 
Morphine is commonly used during therapeutic hypothermia 
The use of opiates such as morphine for management of pain, sedation and shivering 
during TH is quite common due to the critical condition of neonates with HIE (8, 9). 
A recent study showed that up to 64% neonates treated with TH at 125 NICUs 
received opioids (10). Unpublished data from the ongoing High Dose Erythropoietin 
for Asphyxia and Encephalopathy (HEAL) trial demonstrates that out of 501 infants 
with HIE and undergoing TH entered in the study at 17 large NICU centers, 328 
(65%) received morphine in the first 4 days of life (ClinicalTrials.gov NCT02811263).  
However, the use of morphine for sedation during TH has raised concerns for short 
and long-term safety issues including depressed ventilation, hypotension, 
gastrointestinal dysmotility and importantly, possible adverse effects on 
neurodevelopmental outcomes (11-13). In neonatal rats, morphine increased 
apoptosis and lead to long-term negative effects on behavior and brain function 
including impaired motor coordination gait (14-17). 
Dexmedetomidine is neuroprotective in preclinical studies  
Dexmedetomidine is a highly protein-bound drug. In plasma, 94% of 
dexmedetomidine is bound to albumin and α1-glycoprotein. In pre-clinical animal 
studies, it was found that dexmedetomidine readily crosses the blood–brain and 
placenta barriers (31, 32). 
Wang et al studied the neuroprotective action of dexmedetomidine in a mouse 
traumatic brain injury model. Following controlled cortical impact, adult mice 
received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). 
dexmedetomidine treatment decreased neurological dysfunction and brain edema, 
decreased post-traumatic inflammation, up-regulated tight junction protein 
expression, and reduced secondary blood-brain barrier damage and apoptosis. 
Mechanisms implicated included down-regulation of the NF-κB and NLRP3 
inflammasome pathways (31). 
Yin et al. assessed dexmedetomidine neuroprotective functions in early brain injury 
following subarachnoid hemorrhage in adult Sprague-Dawley rats. dexmedetomidine 
(25 µg/kg) or vehicle was administered intraperitoneally 2 h after injury. 

 
 
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Dexmedetomidine treatment improved neurological scores, alleviated brain edema, 
reduced the permeability of the blood-brain barrier and up-regulated the expression 
of tight junction proteins. In addition, dexmedetomidine decreased cell apoptosis at 
24 h after injury. Mechanisms included suppression of the activation of the TLR4/NF-
κB pathway and the NLRP3 inflammasome (33). 
HIE pathophysiology in the newborn shares several of these apoptotic and 
inflammatory pathways, therefore dexmedetomidine may have a role for 
neuroprotection following HIE.  
Dexmedetomidine use in a newborn piglet model of HIE undergoing 
hypothermia 
Ezzati et al reported the PK of dexmedetomidine administered to 9 newborn piglets 
following HIE, in a de-escalation dose study. dexmedetomidine was administered 
with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 down to 
0.6 µg/kg/h. In piglets with plasma concentrations greater than 1 µg /l there were 
periods of bradycardia, hypotension, hypertension, and cardiac arrest. Clearance was 
reduced by 32.7% at a temperature of 33.5 degrees C and by 55.8% following 
hypoxia-ischemia. In this animal model dexmedetomidine clearance was reduced 
almost tenfold compared with adult values. Importantly, high plasma levels of 
dexmedetomidine were associated with cardiovascular complications (34).  
 
Clinical studies: dexmedetomidine is neuroprotective in adult population 
A recent meta-analysis assessed the neuroprotective effects of 
dexmedetomidine on ischemic brain injury in adults. Nineteen RCTs including 879 
patients were included. Results showed that compared with placebo, 
dexmedetomidine reduced the surge of TNF-alpha, neuron-specific enolase, cortisol, 
and glucose as well as decreased the rise in CRP level at postoperative day one. In 
response to stress reaction, dexmedetomidine attenuated the stress-related increase 
of blood pressure, heart rate and intracranial pressure without significant effects on 
cerebral oxygen metabolism. The authors concluded that the use of 
dexmedetomidine could reduce the release of inflammatory mediators and 
neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating 
ischemic brain injury and exerting an effect on brain protection (35). 
Dexmedetomidine studies in the pediatric and neonatal intensive care unit 
populations. Although there is no approved indication in the pediatric population, 
literature reports on pediatric applications of dexmedetomidine have increased in 
number. In 2013 the Dexdor® section on pediatric pharmacology was updated to 
include the use of dexmedetomidine in post-operative pediatric ICU patients 
(>1 month and <17 years) for up to 24 h (36). In children, dexmedetomidine 
appears to exhibit a level of efficacy similar to that seen in adults and to be well 
tolerated.  
The PK of dexmedetomidine in pediatric intensive care patients was evaluated 
by Potts et al. (37), Wiczling et al.(38) and Greenberg et al (39). In these studies, 
dexmedetomidine was delivered via a combination of a short (5 or 10 min) loading 
dose (0.25 to 6 µg/kg/h) followed by a maintenance dose that ranged from 0.2 to 

 
 
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1.4 µg/kg/h. This range in dosing provided adequate sedation without adverse 
effects. However, the authors concluded that immature clearance in the first year of 
life and a higher clearance in small children would require infusion rates that change 
with age.  
In neonates, body composition, fat distribution, and lower protein and albumin 
levels may contribute to a larger volume of distribution and an increased elimination 
half-life. Also, the immaturity of hepatic metabolism can affect dexmedetomidine PK. 
Particularly important to the present study, an immature or dysfunctional blood–
brain barrier may cause higher cerebrospinal fluid concentrations with increased 
sedative and analgesic effects (40). 
Dexmedetomidine efficacy and pharmacokinetics were determined in 24 term (36–
44 weeks) and 18 preterm (28–36 weeks) neonates. Preterm neonates had lower 
weight-adjusted plasma clearance and an increased elimination half-life than term 
neonates. In terms of safety, 56 adverse events (AE) were reported in 26 patients 
(62%) but only 3 (5%) were related to dexmedetomidine. There were no serious AEs 
and no AEs or hemodynamic changes requiring dexmedetomidine discontinuation 
(28). Safety and PK of dexmedetomidine was also studied in cardiac post-operative 
neonatal patients (41). The authors concluded that dexmedetomidine clearance was 
significantly diminished in full-term newborns and increased rapidly in the first few 
weeks of life. In terms of safety, continuous infusions of up to 0.3 mug/kg/h in 
neonates and 0.75 mug/kg/h in infants were well tolerated. More recently, Zuppa et 
al completed a multicenter investigation of dexmedetomidine bolus and infusion in 
122 neonates undergoing corrective infant cardiac surgery (42). The authors 
concluded that using a careful dosing strategy, dexmedetomidine resulted in low 
incidence and severity of adverse safety events. 
Dexmedetomidine PK in neonates with HIE receiving hypothermia 
Recently McAdams et al evaluated PK and safety of dexmedetomidine in a phase I, 
single-center, open-label study in 7 neonates ≥36 weeks' gestational age (GA) 
diagnosed with moderate-to-severe HIE. Infants received a continuous 
dexmedetomidine infusion during TH and the 6 h rewarming period. In cooled infants 
with HIE clearance was either comparable or lower, distribution volume was larger, 
and elimination half-life was longer compared to corresponding estimates previously 
reported for normothermic newborns without HIE as shown in table 1. Plasma 
concentrations in cooled newborns with HIE rose at a slower rate in the initial hours 
of infusion while similar steady-state levels were achieved. There were no acute 
adverse events associated with dexmedetomidine treatment. The authors concluded 
that dexmedetomidine appeared safe for neonates with HIE during TH at infusion 
doses up to 0.4 mug/kg/h.  
 
However, to overcome the initial lag in rise of plasma dexmedetomidine 
concentration a loading dose strategy is strongly suggested and therefore 
included in the present study (18). 
 
 

 
 
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TABLE 1 
McAdams 
(18) 
Chrysostomou 
(28) 
Greenberg 
(39) 
Gestational Age 
(Wks) 
39.6  ± 1.4 
39.1 ± 1.6 
39 (27–40) 
Postnatal Age 
(days, wks) 
1.7 ± 0.5 d 
2.23 ± 1.60 w
ks 
6.14 
(0.57–29) 
wks 
Weight 
3.51 ± 0.54 
3.40 ± 0.60 
4.02 
(2.00–
6.00) 
dexmedetomidi
ne infusion rate 
(µg/k/h) 
0.4 
0.2 
0.5–2.5 
(max) 
Cmax (pg/mL) 
537 ± 180 
968 ± 1011a 
304 ± 49  
Tmax (h) 
31.0 ± 16.8 
NR 
End of 
infusion 
AUC 0-∞ 
(ng/mL.h)  
28.4 ± 8.6 
NR 
NR 
CL (L/h/Kg) 
0.761 ± 0.15
5 
0.907 ± 0.502 
1.23 ± 0.08 
MRT (h) 
6.84 ± 3.20 
4.26 ± 3.90 
1.24 ± 0.09
∗ 
Mean ± SD or median- NR, not reported; Cmax, maximum observed plasma concentration; Tmax, time of 
Cmax; AUC0–∞, area under the plasma concentration-time curve from time 0 to infinity; CL, clearance; 
MRT, mean residence time; ∗p < 0.05 for a 2-tailed, 2-sample t-test between reported values for 
normothermic, non-HIE newborns and observed values for cooled newborns with HIE.  
In conclusion, studies performed in newborn infants demonstrate inter-
individual variability due to factors such as body weight as well as 
significant maturation effects with dexmedetomidine clearance. Thus, 
dexmedetomidine dosing in infants with HIE undergoing TH needs further 
investigation. We propose to determine optimal dosing by collecting 2 
opportunistic PK samples and PRN PK samples any time there is an adverse 
event. 
 
Dexmedetomidine safety in the newborn 
Side effects of dexmedetomidine are mainly restricted to hemodynamic alterations 
including hypertension, bradycardia, and hypotension secondary to pre- and 
postsynaptic α2-receptor activation, which causes vasoconstriction, vasodilatation, 
and reflex bradycardia (43, 44). Importantly, most side effects of dexmedetomidine 
are related to sympatholytic effects and appear to be dose dependent and 
predictable in neonates (45).  
In a retrospective study, O’Mara et al evaluated the effectiveness and short-term 
safety of dexmedetomidine infusion for sedation in 19 term neonates undergoing TH 
for HIE. Initiation of dexmedetomidine infusion did not negatively impact HR, mean 
arterial blood pressures, or cerebral saturations. dexmedetomidine use was not 
associated with any extubation failures or increase need for vasopressors (29). 

 
 
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Of importance to the present proposal is that dexmedetomidine can affect 
thermoregulation by affecting vasoconstriction and non-shivering thermogenesis by 
lipolysis, both key mechanisms present in the newborn infant. Therefore, neonates 
with HIE undergoing TH and receiving dexmedetomidine may be vulnerable to 
abnormal temperature regulation (46, 47).  
In conclusion, safety of dexmedetomidine administration in this particular 
population of critically ill infants with multiorgan failure needs further 
evaluation. We will determine safety during the first 4 days of life by 
documenting potential adverse events such as hypotension, acute renal 
failure, liver failure, poor cardiac function, cardiac arrhythmias, respiratory 
failure, hypothermia, and seizures outside of normal range for the study 
population. 
Potential benefits of Dexmedetomidine use for sedation 
Surkov examined the impact of dexmedetomidine and other sedatives (morphine, 
sodium oxybutyrate, and diazepam) on the cerebral blood flow and clinical outcomes 
in 205 term neonates with HIE. Infants were randomized to receive 
dexmedetomidine (n=46) versus the control group (n=159). Patients in the 
dexmedetomidine cohort were extubated sooner, required lower dose of inotropes, 
had decreased seizure burden and lower incidence of abnormal neuroimaging (48). 
Other potential benefits of using dexmedetomidine versus morphine include time to 
full oral feedings following cessation of TH and need for nasogastric (NG) feedings or 
Gastric Tube (G Tube) at time of discharge. O’Mara et al observed shorter duration of 
parenteral nutrition and time to full oral feedings in babies receiving 
dexmedetomidine for sedation during TH when compared to previously published 
historical patients in their NICU (29). 
In summary, data from clinical dexmedetomidine studies in newborn infants 
is scarce but it indicates that dexmedetomidine used at the appropriate 
dose seems to be a safe sedative agent with a stable hemodynamics profile, 
no adverse cerebral influence, and possible neuroprotective effects in term 
infants with HIE. In the present study we aim to validate this safety profile 
and establish short and long term benefits by assessing 
neurodevelopmental outcomes for this distinct NICU population. 
 
Purpose and Objectives 
Neonatal hypoxia-ischemia encephalopathy (HIE) is the leading cause of neonatal 
death and poor neurodevelopmental outcomes worldwide. Despite early intervention 
using therapeutic hypothermia (TH), current data from recent trials demonstrate 
29% of treated infants either died or had moderate to severe neurologic disabilities 
including long-term motor and cognitive dysfunction. No additional therapies have 
yet proven to be efficacious in further reducing brain injury and impairment for these 
high-risk infants.  Furthermore, additional brain injury may be caused by 
concomitant use of drugs such as morphine to treat pain and sedation in this 
population. Morphine use in animal models has been shown to induce neuronal 

 
 
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apoptosis. Developing adjunctive therapies that improve outcomes in infants with 
HIE is an urgent, unmet public health need. 
Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better 
alternative to morphine for newborns with neonatal encephalopathy treated with TH. 
Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not 
suppress ventilation. Importantly, there is increasing evidence that dexmedetomidine 
has neuroprotective properties in several injury models including ischemia-
reperfusion, inflammation, and traumatic brain injury. Even though there are limited 
data on pharmacokinetics (PK), safety and efficacy of dexmedetomidine in infants 
with neonatal encephalopathy it has been increasingly administered in many centers.  
We hypothesize that dexmedetomidine administered as sedative therapy to infants 
≥36 weeks gestational age with moderate to severe HIE undergoing TH will be safe 
and will be associated with improved short and long-term outcomes. 
To test this hypothesis, we have designed a Phase II multicenter, randomized, safety 
and pharmacokinetics (PK) trial. Fifty infants (n=25 in each arm) ≥36 weeks 
gestational age with HIE will be randomized to receive either dexmedetomidine 
(1 μg/kg for loading dose followed by 0.2 to 0.5 μg/kg/h continuous infusion) or 
morphine (0.02-0.05 mg/kg/dose intermittent dosing q 3 hours IV PRN or as 
continuous infusion dose of 0.005- 0.01 mg/kg/hr). Patients will be stratified by 
severity of encephalopathy (moderate vs. severe).   
We propose the following specific aims: 
Specific Aim 1. To examine safety measures comparing infants receiving 
dexmedetomidine to those administered morphine. The goal of this aim is to 
determine whether there are risks to dexmedetomidine administration in this 
population of infants with neonatal encephalopathy undergoing TH. Safety will be 
evaluated during the first 4 days of life by documenting potential adverse events 
such as hypotension, hypertension, bradycardia, cardiac arrhythmias, hypothermia, 
and seizures outside of normal range for the study population.  Other safety 
measures will be recorded include monitoring standard of care (SOC) labs for events 
such as renal failure or liver failure. 
Specific Aim 2. To further determine dexmedetomidine pharmacokinetics in 
this population of newborns with HIE during treatment with TH. Two to four 
opportunistic PK samples will be obtained for each participant at time of routine 
laboratories. Further PRN PK samples will also be collected any time there is a 
serious or severe adverse event that is at least possibly related to dexmedetomidine 
resulting in holding or discontinuing the dexmedetomidine infusion.  For this study, 
only dexmedetomidine levels will be measured. An additional 0.5mL blood sample 
will be taken in conjunction with standard of care labs during the first 96-120 hours 
of life; this will be 2 to 4 samples (total of 1 to 2 mL) depending on when SOC labs 
are drawn; and total blood volume drawn at any one time and overall will not exceed 
clinical limits. 
Specific Aim 3. To determine whether dexmedetomidine use for sedation versus 
morphine is associated with improved short-term outcomes during initial 
hospitalization (shivering, respiratory support, time to full PO feedings, G tube/NG 

 
 
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feedings at discharge, seizure burden, hearing impairment, MRI); and on long-term 
neurodevelopmental outcomes: 1) Generalized Movement Assessment (cerebral 
palsy assessment) performed 1 week (±2 days) after last dose of morphine or 
dexmedetomidine is given even if beyond treatment period is weaned off or at time 
of hospital discharge whichever happens sooner and at 3-4 months of life; 2) 
Hammersmith Infant Neurological Exam (HINE) performed at 3-4 and at 6-9 months 
of life; 3) Test of Infant Motor Performance (TIMP) performed at 3-4 months of life; 
and 4) Peabody Developmental Motor Skills (PDMS-2) performed at 6-9 months of 
life. The Ages and Stages Questionnaires (ASQ-3) will also be completed by parents 
at the 6-9 months of life visit to screen infants in areas of communication, gross 
motor, fine motor, problem solving, and personal-social. 
Promising preliminary data show that dexmedetomidine might improve outcomes, 
but optimal dosing, safety, and efficacy still need to be established.  We propose to 
confirm dexmedetomidine optimal dosing by collecting opportunistic PK data and 
determine safety of dexmedetomidine in this population in a phase II safety trial. 
These data will inform a larger phase III efficacy trial. 
 
Study Populations 
Age of Participants: Newborns at >36 weeks gestation  
Sample Size: 
At All Sites in Utah: 
50 (received at least one dose of study drug) 
 
Inclusion Criteria: 
• 
Neonates ≥36 weeks’ gestational age diagnosed with moderate-to-severe neonatal 
encephalopathy and treated with TH (target temperature 33.5°C) per unit standard of 
care.  
• 
Infants requiring sedation and/or treatment to prevent discomfort or shivering  
during TH, shown by one of the following criteria: 
o 
As assessed by the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) scores 
and/or a modified Bedside Shivering Assessment Scale; OR 
o 
Continuous infusion of morphine, dexmedetomidine, or another analgesic is 
currently being given as standard care. 
• 
Signed 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 
• 
Maternal use of opioids or opiates (illegal use and or mothers under treatment for opioid 
use) 
 

 
 
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Design 
 
Approach 
This is a Phase II multicenter, randomized, safety and pharmacokinetics (PK) trial. Figure 1 
depicts study design and interventions. Therapeutic hypothermia (TH) and brain MRI will be 
performed per standard of care, and neurodevelopmental impairment (NDI) follow up is also 
done as considered standard of care. Fifty infants (n=25 in each arm) ≥36 weeks GA with 
HIE will be randomized to receive either dexmedetomidine (1 μg/kg for loading dose 
followed by 0.2 to 0.5 μg/kg/h continuous infusion); a continuous morphine infusion of 
0.005-0.01mg/kg/hr; or intermittent dosed morphine 0.02 mg/kg/dose PRN IV q 3 hours up 
to 0.05mg/kg/dose all titrated per NPASS score.  
Initiation and titration of the study drugs should follow the guidelines detailed in figures 2 
and 3.  However, it is always up to the clinical team as to when study drug should be 
started and discontinued based on real-time clinical assessments.  Escalation or weaning of 
study sedation/pain medication and/or use of other sedatives/analgesics is always at the 
discretion of the attending neonatologist and clinical care team.  
Optional Dexmedetomidine Dose Titration 
If dexmedetomidine has reached the maximum of 0.5 µg/kg/h per protocol and optimal 
pain/agitation scores have not been met, the protocol does NOT dictate how the infant 
should be treated and the attending neonatologist can choose to treat the baby per his/her 
discretion. Potential options for patients requiring more than 0.5 ug/kg/hr of 
dexmedetomidine include: ongoing dose escalation of dexmedetomidine up to a maximum 
of 1.0ug/kg/h continuous infusion or the neonatologist may choose to give standard of care 
morphine/alternative analgesic. Whatever option is chosen, it must be approved by the 
attending.  It is important to note that the infant can continue to use study 
dexmedetomidine from the investigational pharmacy through the 96-hour period as needed.   
Optional Morphine Dose Titration 
If intermittent, PRN morphine has reached the maximum of 0.05 mg/kg/dose per protocol 
OR the continuous morphine has reached the maximum of 0.01 mg/kg/hr AND optimal 
pain/agitation scores have not been met, the protocol does NOT dictate how the infant 
should be treated and the attending neonatologist can choose to treat the baby per his/her 
discretion.  Options for patients requiring beyond protocol maximum doses include SOC 
intermittent, PRN morphine doses OR escalation of continuous morphine per SOC.  
The active treatment period for this study is from randomization through 96 hours of life.  Once the 
infant is 96 hours of life, all subsequent treatment for pain/agitation/sedation will be given as 
standard of care.   
 
 
 
 
 
 
 

 
 
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FIGURE 1 
 
 
NDI (neurodevelopmental impairment); MRI (Magnetic Resonance Imaging); GMA (Generalized Movement Assessment);  
HINE (Hammersmith Infant Neurological Exam); TIMP (Test of Infant Motor Performance); PDMS-2  
(Peabody Developmental Motor Skills); ASQ-3 (The Ages and Stages Questionnaires) 
 
Study Sites 
The study will be carried out at four hospitals in Utah: 
1. University of Utah Hospital and Clinics (UUHC), Salt Lake City, Utah 
2. Intermountain Medical Center (IMED), Salt Lake City, Utah 
3. Primary Children’s Hospital (PCH), Salt Lake City, Utah 
4. Utah Valley Hospital (UVH), Provo, Utah 
 
Study Procedures 
Recruitment/Participant Identification Process: 
The study team will be notified by either the charge nurse or attending neonatologist of the 
admitting NICUs when an eligible infant is being transported in or has been born into the 
facility.  The study team will review with the attending neonatologist all of the 
inclusion/exclusion criteria prior to approaching parents for consent. 
 
Informed Consent: 
1) In the Newborn ICU where the study is being carried out or 
2) In the event of a transport, consent may take place in the referring hospital/ delivery 
center via the transpot team and/or via econsent/facsimile/phone. 
 
Description of the consent process(es), including the timing of consent: 
There is no obligatory waiting period for the consent to be obtained (other than allowing the 
parents time to ask questions and discuss the study between themselves and/or other family 
members). There is a time frame for consent (within 24 hours of birth) for the infant to receive 
the investigational drug as early as possible. 
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Procedures: 
After eligibility is confirmed, with approval from the Attending Care Provider, the parent or legal 
guardian will be approached for consent. All patients eligible for this study will be managed in 
the NICU. 
Telephone/Electronic Consent  
Newborn patients are frequently transfered to the NICUs at the University of Utah, Primary 
Children’s Medical Center, Intermountain Medical Center, or Utah Valley Hospital, for 
treatment with TH. In an effort to approach for the study as soon as possible, the transport 
team may give the potential eligible parents or legal guardians a brochure and/or a full hard 
copy of the consent form, explaining that if their baby meets criteria for the DICE trial, the 
research team may contact them with more information. 
If the transport team does not have a hard copy of the consent, the research team will send 
a copy of the consent via facsimile to the hospital/ delivery center where the parents/legal 
guardians are physically located or electronically directly to the parents if the parents have 
given the research team verbal permission to send it. 
Phone consent for the study will be done by the research team or neonatologist on service 
or on call in the NICU. The study and its options will be explained to the parent(s) ensuring 
that they know this is a voluntary study and they are in no way obligated to participate. 
They will be allowed time to ask questions over the phone and will be able to read the 
consent document as it is discussed. If they give their consent, one parent can provide 
written consent either by signing the paper consent or by e-consent.  Study procedures will 
begin only after signed consent has been received by the study team. This can be a paper 
consent given to the transport team, e-consent, or a copy of the signed paper consent 
provided to the study team by email, text, fax, etc.  
Interventions 
All infants admitted to the NICU at a study site with a diagnosis of HIE and undergoing TH 
will be screened for the study. If the infant meets eligibility criteria and the attending 
physician agrees to the patient’s entry into the study, the parents will be approached for 
informed consent. Time for obtaining consent is up to 24 hours of age. TH should be done 
as standard of care per unit guidelines via whole body hypothermia using a servo 
mechanism. 
Randomization Procedures 
Eligible infants with informed consent will be randomized to receive either dexmedetomidine 
(1 μg/kg for loading dose followed by 0.2 to 0.5 μg/kg/h continuous infusion); a continuous 
morphine infusion of 0.005-0.01mg/kg/hr; or intermittent dosed morphine 0.02 mg/kg/dose 
PRN IV q 3 hours up to 0.05mg/kg/dose.  
  
Randomization will be stratified by severity of encephalopathy. A variable permuted, block 
size will be used.  Centralized randomization will be managed by the Data Coordinating 
Center at the University of Utah. 

 
 
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NOTE:  Infant is not enrolled into the study until infant is randomized. If an infant is 
randomized and then does not receive at least one dose of study drug by 96 hours of life or 
prior to death (if occurs < 96 hours of life), this infant is not considered evaluable and will be 
withdrawn from the study and no further interventions or data will be collected.  Infant will be 
replaced with another subject.  We will replace subjects until we have at least 50 evaluable 
subjects. 
Study Drug Administration 
 
Dexmedetomidine hydrochloride injection (4 mcg/mL base) or continuous morphine sulfate 
(at NICU concentrations per standard of care institutional practices  mg/mL) will be 
administered in a primed intravenous line via a computer-controlled infusion device 
programmed by trained NICU nurses. Morphine sulfate (at NICU concentrations per 
standard of care institutional practices) may also be given as bolus intermittent dosing.  The 
initial study drug dose should be given once NPASS or BSAS scores are met after 
randomization and no later than 96 hours of age. There is no defined time interval between 
a qualifying NPASS or BSAS score and initiation of study drug. Therefore, for those infants 
not receiving any drug/s for pain/sedation management prior to randomization, the most 
recent score(s) obtained prior to the study drug initiation must be a qualifying score (NPASS 
≥4 and/or BSAS ≥2).  If morphine, dexmedetomidine, or another analgesic drug is already 
infusing continously prior to study drug initiation, no qualifying NPASS or BSAS is required 
in order to start study drug.  Transition from ongoing continuous infusions to study drug 
infusion or bolus dosing will be done per attending and PI preference and can begin any 
time after randomization.  Any open-label analgesic given during transition period will not 
be considered a deviation. 
 
NOTE:  Continuous dosing of either dexmedetomidine or morphine will require an IV that is 
not also being used for intermittent medications that require flushing before or after infusion 
of the intermittent medication.  
Initiation and adjustment of the dexmedetomidine and morphine doses (i.e., 
increasing, decreasing, or holding the dose) during TH will be based on the algorithm in 
figures 2 and 3. To standardize clinical management during the trial, the Neonatal Pain, 
Agitation, and Sedation Scale (N-PASS) and the Bedside Shivering Assessment Scale 
(BSAS) scores will used prior to and during dexmedetomidine and morphine exposure to 
determine sedation and analgesia effectiveness of both drugs (49, 50).  
The N-PASS tool uses 5 assessment criteria (crying/irritability, behavior/state, facial 
expression, extremities/tone, and vital signs); each criterion is graded 0, –1, or –2 for 
sedation and 0, 1, or 2 for pain/agitation and these two scores are calculated independently. 
A pain/agitation score >3 is considered to reflect significant pain or agitation, at which point 
supplemental sedation or analgesia therapy will be administered/escalated following the 
algorithm in figure 2. A sedation score of less than -2 indicates light sedation and warrants 
consideration for therapy weaning, a score less than -5 warrants weaning.  This is shown in 
Table 2. 
 
 

 
 
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TABLE 2 
 
Pain and sedation will be assessed a minimum of every 3-4 hours ±30 min (at the time of 
vital signs assessments) as well as 30-60 minutes post escalation or de-escalation of 
medication. Escalation or weaning of study sedation/pain medication and/or use of other 
sedatives/analgesics is always at the discretion of the attending neonatologist.  Open-label 
morphine will be available for rescue analgesia or to prevent shivering as per the discretion 
of the medical team (incidence, dose, and duration of treatment with adjunctive sedation 
medications will be recorded).   
The BSAS is a 4-point scale that rates the severity of shivering, shown in Table 3. 
 

 
 
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TABLE 3   
 
Both dexmedetomidine and morphine can be used to treat shivering and study doses can be 
adjusted based on the shivering score.  It is important to note that non-pharmacological 
interventions are not used to treat shivering, so in the Figures 2 and 3, this step is skipped 
when treating shivering. 
Figures 2 and 3 are the guidelines that will be used to determine the dosing of the study drug.  
Although it is highly preferred for the clinical team to use the guidelines as presented, it is 
always up to the clinical team as to when study drug should be started and discontinued based 
on real-time clinical assessments.  Escalation or weaning of study sedation/pain medication 
and/or use of other sedatives/analgesics is always at the discretion of the attending 
neonatologist and clinical care team.  Advancing or decreasing the rate/dosage of the study 
drug in different increments from the guidelines is allowed and not considered a deviation.  
Additionally, administration or escalation of a study drug dose prior to a painful/uncomfortable 
procedure/intervention is allowed and not considered a deviation.  Documentation of all study 
drug administration and discussions by the clinical team regarding study drug administration 
are charted in the electronic healthcare records per unit protocol. 
Study drug may be allowed to infuse longer than 96 hours of age if needed for short term 
clinical purposes, such as conducting the SOC MRI.  Study drug can continue infusing until 
clinical dexmedetomidine or morphine can be ordered or, if needed short-term for a 
procedure, procedure is completed (without a clinical order).  A clinical order will be 
required if the continuous study drug is needed for longer than 6 hours after the 96 hours of 
life (study treatment period). 
 
 
 
 
 
 

 
 
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FIGURE 2 
 
 
 

 
 
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FIGURE 3 
 
 

 
 
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Dose Justification 
Based on previous studies (see preliminary data section; table 1) in this population and 
standard of care practices, infants will be randomized to receive either dexmedetomidine 
(1 μg/kg for loading dose followed by 0.2 to 0.5 μg/kg/h continuous infusion); a continuous 
morphine infusion of 0.005-0.01mg/kg/hr; or intermittent dosed morphine 0.02 mg/kg/dose 
PRN IV q 3 hours up to 0.05mg/kg/dose (18). All are titrated based on NPASS or BSAS 
scores. 
Outcomes and data to be collected 
Primary outcome for this proposal will be safety.  
Primary Safety Endpoints: 
1) Cardiovascular  
Adverse events will be defined as follows: 
     -Severe bradycardia (heart rate <60 sustained for >30 minutes) 
     -Severe tachycardia or other cardiac arrythmias (arrhythmia requiring treatment) 
-Severe hypotension (mean blood pressure (BP) <30 or decrement in mean BP >20-30 
OR receiving volume therapy >40-80 ml/kg during a 24 h period OR escalation of 
vasoactive inotropic score by > 30 compared to baseline)     
     -Severe hypertension (>2SD normal mean blood pressure and requiring treatment) 
2) Temperature 
     -Severe hypothermia will be defined as esophageal temperature <31 C for >30 minutes 
3)  Increased seizure burden (>4 hours of electrographic seizure burden in the first 24 
hours after birth) 
 
Secondary outcomes will include short and long-term clinical aspects during initial 
hospitalization as well as during neurodevelopmental follow up.   
These efficacy outcomes will include: 
  - Respiratory support (need for nasal cannula, CPAP, invasive mechanical   
        ventilation/modality) and time to extubation 
- Incidence of shivering 
- Time to full PO feedings (days) 
- G tube/NG feedings at hospital discharge 
- Duration of central venous and arterial access 
- Neurologic exam at 7 days of life  
- Hearing screen results 
- Brain MRI, Head US 
- aEEG and Video EEG 
- Need for other medications (antibiotics, steroids, other sedatives, or opiates) will be 
systematically collected 
 
For long-term neurodevelopmental outcomes, follow up will include: 
1) Generalized Movement Assessment (GMA) performed 1 week (±2 days) after 
sedation is weaned off or before discharge if less than 7 days: and at 3-4 months (±1 
month) of life.  
2)  Hammersmith Infant Neurological Exam (HINE) performed at 3-4 months (±1 
month) and at 6 to 9months (±1 month) of life. 
3)  Test of Infant Motor Performance (TIMP) performed at 3-4 months (±1 month) of 
life. 
4)  Peabody Developmental Motor Skills (PDMS-2) at 6-9 months (±1 month) of life. 

 
 
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5) The Ages and Stages Questionnaires (ASQ-3) will also be completed by parents at  
the 6-9 months (±1 month) visit. 
 
Case report forms will be developed to collect maternal characteristics (including labor & 
delivery details), neonatal characteristics including NICU assessments, and primary and 
secondary outcomes. Neonatal data will include gestational age, birth weight, gender, Apgar 
scores, delivery room resuscitation, and pertinent details of the hospital course. 
 
Procedures performed for research purposes only:  
Study drug (dexmedetomidine) 
PK levels of blood (for infants randomized to and have received dexmedetomidine only) 
Statistical Methods, Data Analysis, and Interpretation 
Sample size and resulting power  
The primary outcome in this proposal will be safety as described on page 10. Secondary 
outcomes will include short and long-term clinical aspects including initial hospitalization 
(shivering, respiratory support, time to full oral feedings, G tube or tube feedings at discharge, 
seizure burden; neurologic exam at 7 days of life, MRI) as well as neurodevelopmental follow 
up.  
 
For the sample size calculation, 50 evaluable subjects (25 in each arm) would yield 80% 
power to compare dexmedetomidine relative to Morphine for key safety measures using 
tolerance limits of 0.5 SDs for quantitative measures of organ function. This sample size is 
also considered adequate to evaluate neurodevelopmental outcomes explored in this 
proposal as secondary outcomes. Lastly, the sample size of 50 is adequate to evaluate 
feasibility for a potential phase III trial. For the analysis of safety effect, we will use an 
intention-to treat strategy. To compare adverse event and serious adverse event counts 
between treatment groups we will use a Poisson regression model with robust SEs adjusting 
for the severity of encephalopathy. To calculate the effect of dexmedetomidine versus 
morphine on developmental outcome measures, we will use 95% confidence intervals, and 
corresponding P values (significance, P < .05) using a linear regression with robust SEs, 
with and without adjusting for age at testing and for severity of encephalopathy at baseline. 
All statistical analyses will be performed by an independent biostatistician. 
 
Methodology 
Specific Aim 1- Safety 
To examine safety measures comparing infants receiving dexmedetomidine with infant 
administered morphine. The goal of this aim is to determine whether there are risks to 
dexmedetomidine administration in this population of infants with HIE undergoing hypothermia.  
 
An adverse event (AE) will be defined as any adverse change from the patient’s baseline 
condition that occurred following the first administration of the study drug through the end of 
the study period. Safety will be evaluated during the first 4 days of life by documenting 

 
 
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potential adverse events such as (but not limited to) severe hypotension, severe hypertension, 
severe hypothermia, acute renal failure, liver failure, cardiac arrhythmias, and seizures outside 
of normal range for the study population. 
 
Serious adverse events (SAE) will be defined as any event that results in: death, a life-
threatening event (severe cardiac arrythmia), persistent or significant disability/ incapacity, 
and/or prolongs inpatient hospitalization. SAEs will be reported until 7 days following final dose 
of study drug during the treatment period or until hospital discharge, whichever comes first. 
 
Sample size and resulting power  
For the sample size calculation, 50 evaluable subjects (25 in each arm) would yield 80% power 
to compare dexmedetomidine relative to Morphine for key safety measures using tolerance 
limits of 0.5 SDs for quantitative measures of organ function. The sample size of 50 would be 
adequate to evaluate feasibility for a potential phase III trial. To compare AEs and SAEs counts 
between treatment groups we will use a Poisson regression model with robust SEs adjusting for 
the severity of encephalopathy.  
 
Data Safety Monitoring Committee (DSMC)  
An independent Data Safety and Monitoring Committee (DSMC) will monitor study progress, 
safety, and efficacy. The DSMC is composed by study monitors qualified by training and 
experience to monitor the progress of the investigation. An interim safety analysis will be 
performed after a total of 10 infants are enrolled. 
The trial will be temporarily suspended for the initial safety look and as deemed necessary by 
the DSMC for any subsequent safety concerns.  
 
Serious Adverse Events (SAEs) reporting 
All SAEs will be reported to the site PI within 24 hours of learning of the event. The PI will be 
responsible for reporting the unanticipated adverse events 1) to the local IRB in accordance 
with the local IRB policies; 2) to the DSMC chair within 24 hours of receiving the report; 3) to 
the FDA in an IND safety report in accordance with FDA regulations; and 4) to all participating 
site PI’s. The DSMC will determine if the adverse event changes the risk to study subjects. If 
the information changes the known risk to subjects, the DSMC report of this event will be 
released to all participating investigators by the PI. 
 
Criteria for withholding or stopping the study drug-Dexmedetomidine only 
Criteria for withholding or stopping dexmedetomidine will be the occurrence of an adverse 
reaction requiring intervention (one or more of the following):  
1) Severe bradycardia (heart rate <60 sustained for >30 minutes) 

 
 
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2) Severe tachycardia or other cardiac arrythmias (atrial fibrillation) requiring 
treatment 
3) Severe hypotension (<30mm Hg mean arterial pressure) OR decrement in 
mean BP >20 to 30 mmHg compared to baseline OR receiving volume therapy 
> 40 to 80 ml/kg during each 24 h period of the study monitoring period: OR 
escalation of vasoactive inotropic score by > 20 to 30 compared to baseline  
4) Severe hypertension (sustained SBP >95th centile) requiring treatment. 
5) Severe hypothermia (esophageal temperature <31 C) for > 30 min 
6) Infant placed on ECMO 
7) And at the discretion of the attending physician after consultation with the 
study/site PI.   
 
Following holding or stopping, study dexmedetomidine may be restarted per PI and attending 
physician discretion while the infant is within the study treatment period (within 96 hours of 
age). When restarting dexmedetomidine, a loading dose will not be repeated, and the starting 
infusion rate will be at the discretion of the attending as long as it is within protocol limits. 
If the decision is made not to restart dexmedetomidine, further management will proceed per 
usual care at the site.  
NOTE:  Withholding or discontinuing morphine for adverse events is at the discretion of 
the attending neonatologist per unit standard of care. 
 
Study Halting Rules 
Enrollment and study drug administration will be halted for DSMC review, but PK sampling and 
follow-up will continue, if any of the following are reported: 
• 
Death of a subject receiving Dexmedetomidine infusion and prior to the subject’s 
hospital discharge that was not the result of moderate or severe hypoxia ischemia 
encephalopathy (HIE) and associated multiorgan disfunction, regardless of relatedness 
to study product. The incidence of intrahospital death for patients with HIE is 10% in the 
most recent reports. 
• 
Occurrence of an allergic/hypersensitivity reaction (anaphylaxis) in any subject during 
the drug infusion manifested by bronchospasm with or without urticaria or angioedema 
requiring hemodynamic support with pressor medications or mechanical ventilation.  
• 
Two or more subjects with a new Grade 3 or higher AE that is at least possibly related to 
study drug. 
 
Laboratory: Data from clinical laboratory studies that are routinely assessed in infants undergoing 
cooling (first 72 hours) will be collected as part of the present study, including: liver and renal 
function, troponin, hematocrit level, white cell count, platelet count, PT, PTT, fibrinogen, and d-
dimer.  This data will be collected through discharge.  
Other data to be collected include brain imaging studies (Cranial US, MRI) as SOC during hospital 
stay. 

 
 
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Specific Aim 2 
Pharmacokinetics 
The objective of this specific aim will be to determine dexmedetomidine PK in this population of 
newborns with HIE during treatment with TH and rewarming periods (Day 1-4). PKs will only be 
drawn and analyzed in babies randomized to AND receive dexmedetomidine. 
Blood Samples-Dexmedetomidine arm only 
To avoid excessive phlebotomy losses, a sparse sampling strategy analysis will be employed. Two to 
four opportunistic blood samples (0.5 mL) will be obtained for each participant at the time of routine 
laboratories.  Further PRN PK samples will also be collected any time there is a serious or severe 
adverse event that is at least possibly related to dexmedetomidine resulting in holding or 
discontinuing the dexmedetomidine infusion. An additional 0.5mL blood sample will be taken in 
conjunction with standard of care labs during the first 96-120 hours of life; this will be 2 to 4 
samples (total of 1 to 2 mL) depending on when SOC labs are drawn; and total blood volume drawn 
at any one time and overall will not exceed clinical limits.  Blood samples will be centrifuged and the 
plasma frozen at -80°C until shipping. Collected samples will be shipped/transported in batches to 
Frontage Laboratories for analysis. 
 
Dexmedetomidine HPLC-MS/MS analysis for PK samples  
Dexmedetomidine concentrations in plasma will be quantified using a validated HPLC-MS/MS assay. 
Accuracy and precision are within the Food and Drug Administration bioanalytical assay validation 
criteria (e.g., ±15%). The lower limit of quantification is 5 pg/mL. This method was successfully 
employed in a PK study of dexmedetomidine in neonates and infants after cardiac surgery (51).  
Pharmacokinetic Analysis  
Dexmedetomidine plasma PK data will be analyzed with a nonlinear mixed effects modeling approach 
using NONMEM (version 7.4, Icon Solutions, Ellicott City, MD, USA). One- and two-compartment PK 
models will be explored. Between-subject variability will be assessed for PK model parameters using 
an exponential relationship. Both diagonal and block Omega matrices for covariance will be explored. 
Proportional, additive, and combined (additive plus proportional) residual error models will be 
explored. Bodyweight (WT) will be included as a covariate for clearance (CL) and volume of 
distribution (V) in the base model. The relationship between WT and PK parameters will be 
characterized using a fixed exponent (0.75 and 1) for CL and V parameters, respectively. Other 
covariates will be tested for model inclusion based on physiological relevance and by visual 
inspection of scatter and box plots. The relationship between age and CL will be explored using a 
sigmoidal maximum efficacy (Emax) maturation function as shown in equation (1). As a measure of 
age, PNA and PMA were explored.  
 
(1) 
 

 
 
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where Fage denotes the fraction of the adult CL value; TM50 represents the value of age (days for PNA 
and weeks for PMA) when 50% adult CL is reached; and Hill (Hill coefficient) is a slope parameter for 
the sigmoidal maturation model.(52) A forward inclusion (p<0.05) and backward elimination 
(p<0.01) approach will be used to evaluate statistical significance. 
 
Models will be evaluated based on successful minimization, diagnostic plots, plausibility, and 
precision of parameter estimates, as well as objective function value (OFV) and shrinkage values. 
Parameter precision for the final model will be evaluated using non-parametric bootstrapping 
(1000 replicates) to generate the 95% confidence intervals for parameter estimates. Visual 
predictive check (VPC) will be performed whereby the final model will be used to generate 1000 
Monte Carlo simulation replicates per time point of dexmedetomidine exposure. The number of 
observed concentrations outside of the 90% prediction interval for each time point will be quantified. 
Monte Carlo simulations will be used to evaluate different dosing regimens and calculate the 
probability of achieving the target exposure. 
Specific Aim 3  
Clinical and Neurodevelopmental Outcomes 
Secondary efficacy outcomes will include short and long-term clinical aspects collected during initial 
hospitalization as well as during neurodevelopmental follow up.  
1) To determine whether dexmedetomidine use for sedation versus morphine is associated with 
improved short-term clinical outcomes during initial hospitalization the following data will be 
collected: 
- Respiratory support: 
The need for Nasal Cannula, High Flow Nasal Cannula, CPAP, invasive mechanical 
ventilation/modality; and time to extubation will be recorded. 
-Shivering: 
Shivering will be assessed and recorded using an adapted version of the Bedside Shivering 
Assessment Scale (Badjatia et al.)(53). This tool has only been validated in brain-injured adults but 
used in neonates successfully (18). It consists of a 4-point scale which rates shivering as none: no 
shivering noted (0), mild: shivering localized to the neck and/or chest only (1), moderate: shivering 
involves upper extremities, plus neck and chest (3), or severe: shivering involves whole body (4). 
Shivering scores will be recorded along with the date, time, and duration of the episode and whether 
morphine was given. 
- Duration of central venous and arterial access 
- Time to full PO feedings 
- Need for G tube/NG feedings at discharge 
- Neurologic exam: Performed at 7 days of life (±2 days) or prior to discharge 
- Brain MRI, Head US 

 
 
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- aEEG and Video EEG 
- Hearing Screen  
- Need for other medications (antibiotics, steroids, other sedatives, or opiates) will be 
systematically collected) 
2) To determine whether dexmedetomidine use for sedation versus morphine is associated with 
improved neurodevelopmental outcomes at time of follow up the following data will be collected: 
Neurodevelopmental outcomes are typically assessed as SOC and include the following exams:  
Generalized Movement Assessment (GMA) at 3-4 months of life (±1 month); the Hammersmith 
Infant Neurological Examination (HINE) at 3-4 and 6-9 months of life (±1 month); the Test of Infant 
Motor Performance (TIMP) performed at 3-4 months (± 1 month) of life; and 4) the Peabody 
Developmental Motor Skills (PDMS-2) at 6-9 months (± 1 month) of life.  Data will be collected for 
the study from these exams. There may be circumstances in which a test listed above is not done as 
part of the standard of care visit and this will not be considered a deviation.  These tests will be used 
as markers of neurodevelopmental safety in the assessment of dexmedetomidine versus morphine. 
The ASQ-3 will also be completed by parents at the 6-9 month (±1 month) visit to screen infants in 
areas of communication, gross motor, fine motor, problem solving, and personal-social. 
The GMA, HINE, TIMP, and PDMS-2 are established, validated tests of neurodevelopment in both low 
and high-risk infants. The combination of GMA, HINE and TIMP are core components of the 
neurodevelopmental assessment for early diagnosis of cerebral palsy (CP)(54-56). In a systematic 
review by Novak et al, the most predictive tools for detecting CP risk before 5 months’ corrected age 
were term-age MRI (86%-89% sensitivity), the GMA (98% sensitivity), and the HINE (90% 
sensitivity). After 5 months’ corrected age, the most predictive tools for detecting risk were MRI 
(86%-89% sensitivity), and the HINE (90% sensitivity)(56). 
 
The HINE optimality score is based on the frequency distribution of neurological findings in a typical 
infant age group, when an item is found in at least 90% of infants it is considered optimal. Use of the 
HINE at 3-4 and at 6-9 months of age allows for multiple assessments of motor development. A cut 
off of 57 is used to identify infants at 3 months who are high risk for CP and those infants are 
followed with an additional visit at 6 months of age. Total HINE scores as well as asymmetries will be 
assessed and compared between treatment groups.   
 
The GMA will be assessed as a dichotomous variable (fidgety present or fidgety absent/abnormal 
fidgety before hospital discharge when off sedation and repeated at 3-4 months of life).   
The ASQ-3 screening tool has been validated in several studies and is recommended by the AAP as 
one of the developmental surveillance and screening tests (57). Psychometric studies based on a 
normative sample of more than 18,000 questionnaires showed high reliability, internal consistency, 
sensitivity, and specificity.   
All infants will be followed up at the University of Utah Neonatal Follow Up Program. The Neonatal 
Follow-up Program is well suited to provide follow up for this study. In addition to providing 
neurodevelopmental assessments for high-risk neonates it is one of 6 universities nationally that has 
partnered with the Cerebral Palsy Foundation and Nationwide Children’s Hospital in the Early 
Detection of CP and has extensive expertise in the GMA, HINE, TIMP, and PDMS-2.   

 
 
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Statistical Analyses 
The sample size of 50 evaluable (25 infants in each study arm) was determined to provide sufficient 
evidence regarding the equivalence or noninferiority of dexmedetomidine relative to morphine for 
key safety measures and is also considered adequate to evaluate neurodevelopmental outcomes 
explored as secondary outcomes. Any infants who are enrolled and randomized, but who do not 
receive a study drug dose will not be included in the analysis and another infant will be recruited for 
randomization. To calculate the effect of dexmedetomidine versus morphine on developmental 
outcome measures, we will use 95% confidence intervals, and corresponding P values (significance, 
P < .05) using an appropriately developed generalized regression with robust SEs, adjusting as 
appropriate with patient covariates, including, potentially age at testing and severity of 
encephalopathy at baseline. Variable selection will be based on corrected Akaike Information 
Criterion (AICc) for an all-subsets selection technique. 
 
For summary statistics, we will compare categorical variables between randomized treatment groups 
by using a χ2 test, or Fisher’s exact test when the expected count of any category is ≤5. To compare 
baseline continuous variables between treatment groups, a two-sided t test will be used. All 
statistical analyses will be performed by an independent biostatistician by using statistical software.  
 
Additional Follow-up Assessments 
No additional follow-up assessments are planned for this protocol after the 9 months assessment; 
however, consent for future contact will be sought if additional follow-up of the study participants is 
conceived. Future follow-up will require informed consent and appropriate institutional and regulatory 
approval. 
 
Annual Reports 
Annual Reports are required on all active IND applications. If the IND is placed in inactive status, 
annual reports are not required. (21 CFR 312.45(c)). Annual reports are required to be submitted to 
the FDA within 60 days of the anniversary of the date that the IND went into effect (21 CFR 212.33). 
Please update the protocol to address annual reporting. 
 
Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated without 
submission of an amendment for IRB review and approval. Any amendments to the protocol that 
significantly affect the safety of subjects, the scope of the investigation, or the scientific quality of 
the study are required to submit the amendment for FDA review. 
 

 
 
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Record Retention 
Records will be maintained at the study site per, 21 CFR 312.57. A sponsor shall retain the study 
records and reports for 2 years after a marketing application is approved for the study drug; or, if an 
application is not approved for the drug, until 2 years after shipment and delivery of the drug for 
investigational use is discontinued and FDA has been so notified.  
Protocol Violations and Deviations 
All applicable protocol violations and deviations will be reported within guidelines set forth by the 
governing Institutional Review Board.  
A deviation is any departure from the defined procedures and treatment plans as outlined in the 
protocol version or application version submitted and previously approved by the Institutional Review 
Board. 
 
 
 

 
 
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