Dexmedetomidine for Neonatal Encephalopathy
(DICE Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
MB
Overseen byMariana Baserga, MD
Age: < 18
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of Utah
Disqualifiers: Chromosomal anomalies, Heart defects, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
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.
Will I have to stop taking my current medications?
The trial information does not specify whether participants must stop taking their current medications. It is best to consult with the trial coordinators for specific guidance.
What data supports the effectiveness of the drug Dexmedetomidine for treating neonatal encephalopathy?
Dexmedetomidine is known for its neuroprotective properties and is used as a sedative and pain reliever in critical care. It may be a better alternative to morphine for newborns with neonatal encephalopathy undergoing therapeutic hypothermia, as it provides sedation and pain relief without suppressing breathing, and has shown potential in improving outcomes in preclinical studies and adult brain trauma trials.12345
Is dexmedetomidine safe for use in humans, particularly in neonates?
Dexmedetomidine has been shown to be safe in the short term for neonates, with some studies reporting side effects like bradycardia (slow heart rate) and hypotension (low blood pressure). More research is needed to understand its long-term safety, but it is considered a promising alternative to morphine for sedation and pain management in newborns.14567
What makes the drug Dexmedetomidine Hydrochloride and Morphine Sulfate unique for treating neonatal encephalopathy?
Dexmedetomidine Hydrochloride is unique because it acts as a sedative with potential neuroprotective effects, which may help in managing neonatal encephalopathy by reducing brain inflammation and injury. Morphine Sulfate is commonly used for pain relief, and its combination with Dexmedetomidine may offer a novel approach to managing symptoms and improving outcomes in affected newborns.89101112
Research Team
MB
Mariana Baserga, MD
Principal Investigator
University of Utah
Eligibility Criteria
This trial is for newborns at least 36 weeks old with moderate-to-severe brain injury from lack of oxygen and undergoing cooling therapy. They need sedation or shiver prevention, as judged by specific pain and shivering scales. Babies with genetic anomalies, critical conditions leading to care redirection, or certain heart defects cannot join.Inclusion Criteria
My newborn, at least 36 weeks old, has severe brain dysfunction and is undergoing cooling treatment.
My infant needs medication to stay calm or stop shivering during treatment.
Informed consent document approved by the Institutional Review Board (IRB) obtained prior to randomization
Exclusion Criteria
I have a known genetic abnormality.
You are seriously ill and are considering changing your treatment plan, or have decided not to receive full medical support.
I have a heart defect present from birth that causes bluish skin.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Treatment
Participants receive either dexmedetomidine or morphine for sedation and pain management during therapeutic hypothermia
First 96 hours of life
Continuous monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessments of motor performance and neurological function
Up to 9 months
Multiple assessments at 3-4 months and 6-9 months of age
Extension
Long-term follow-up to assess developmental outcomes using various neurological and motor assessments
Up to 9 months
Treatment Details
Interventions
- Dexmedetomidine Hydrochloride (Alpha-2 Agonist)
- Morphine Sulfate (Opioid Analgesic)
Trial OverviewThe DICE Trial is testing the safety and dosing of Dexmedetomidine (DMT) compared to Morphine for managing pain and sedation in infants receiving therapeutic hypothermia for brain injuries due to oxygen deprivation. It's a Phase II study that will set the stage for a larger efficacy trial.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: Dexmedetomidine (DMT)Experimental Treatment1 Intervention
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.
Group II: MorphineActive Control1 Intervention
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.
Dexmedetomidine Hydrochloride is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Precedex for:
- Sedation for mechanically ventilated patients
- Procedural sedation
- Acute agitation associated with schizophrenia or bipolar disorder
🇪🇺 Approved in European Union as Dexdor for:
- Sedation for mechanically ventilated patients
- Procedural sedation
🇨🇦 Approved in Canada as Dexmedetomidine Hydrochloride for:
- Sedation for mechanically ventilated patients
- Procedural sedation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Intermountain Medical CenterMurray, UT
Primary Children's HospitalSalt Lake City, UT
Utah Valley HospitalProvo, UT
University of Utah HealthSalt Lake City, UT
More Trial Locations
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Who Is Running the Clinical Trial?
University of Utah
Lead Sponsor
Trials
1169
Patients Recruited
1,623,000+
References
Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects. [2021]Dexmedetomidine (Dexdor or Precedex®) is considered as a sedative agent which is widely used as an adjuvant in general anesthesia and critical care practice. There is extensive evidence indicating its neuroprotective properties especially in various ischemic and hemorrhagic brain injury models of animals. Clinical trials have shown that dexmedetomidine (DEX) can improve the outcome of intensive care unit (ICU) patients. Also, DEX is appropriate as a non-opioid analgesic therapy whenever minimizing opioid-related side effects is necessary. The present article reviews the recent advances in the use of DEX as a neuroprotective agent in both animal and human studies including newest findings about the mechanism of the drug as well as analgesic efficacy of this drug at all perioperative stages. In spite of the beneficial effects of the drug on the nervous system, there are potential adverse effects, such as hypotension and bradycardia, which can be treated pharmacologically and must be taken into consideration by clinicians.
Epileptic seizures induced by dexmedetomidine in a neonate. [2013]Dexmedetomidine hydrochloride, a highly selective 2-adrenoceptoragonist, is used in combination with local anesthetics for sedation and analgesia. It is known to be efficacious in adult patients and is enthusiastically expected to be successful for sedation in neonates.
Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. [2022]To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates.
Hemodynamic effects of dexmedetomidine in patients after cardiac surgery. [2006]Dexmedetomidine hydrochloride (Prece-dex(R)) is a potent and highly selective central a2-adrenoreceptor agonist. Dexmedetomidine has recently been approved as a new sedative drug, however, its hemodynamic effects on patients just after cardiac surgery has not been established.
Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial): A Randomized Controlled Trial: Background, Aims and Study Protocol. [2022]Background: Neonatal hypoxia-ischemia encephalopathy (HIE) is the leading cause of neonatal death and poor neurodevelopmental outcomes worldwide. Therapeutic hypothermia (TH), while beneficial, still leaves many HIE treated infants with lifelong disabilities. Furthermore, infants undergoing TH often require treatment for pain and agitation which may lead to further brain injury. For instance, morphine use in animal models has been shown to induce neuronal apoptosis. Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better alternative to morphine for newborns with HIE 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. Even though there are limited data on pharmacokinetics (PK), safety and efficacy of dexmedetomidine in infants with HIE, it has been increasingly administered in many centers. Objectives: To review the current approach to treatment of pain, sedation and shivering in infants with HIE undergoing TH, and to describe a new phase II safety and pharmacokinetics randomized controlled trial that proposes the use of dexmedetomidine vs. morphine in this population. Methods: This article presents an overview of the current management of pain and sedation in critically ill infants diagnosed with HIE and undergoing TH for 72 h. The article describes the design and methodology of a randomized, controlled, unmasked multicenter trial of dexmedetomidine vs. morphine administration enrolling 50 (25 per arm) neonates ≥36 weeks of gestation with moderate or severe HIE undergoing TH and that require pain/sedation treatment. Results and Conclusions: Dexmedetomidine may be a better alternative to morphine for the treatment of pain and sedation in newborns with HIE treated with TH. There is increasing evidence that dexmedetomidine has neuroprotective properties in several preclinical studies of injury models including ischemia-reperfusion, inflammation, and traumatic brain injury as well as adult clinical trials of brain trauma. The Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE) trial will evaluate whether administration of dexmedetomidine vs. morphine is safe, establish dexmedetomidine optimal dosing by collecting opportunistic PK data, and obtain preliminary neurodevelopmental data to inform a large Phase III efficacy trial with long term neurodevelopment impairment as the primary outcome.
Dexmedetomidine - An emerging option for sedation in neonatal patients. [2022]Dexmedetomidine is a sedative agent with limited dosing, safety, and efficacy information in the neonatal population. This comprehensive review describes the available evidence summarizing the use of dexmedetomidine in various neonatal populations. We identified 21 studies and 1 case report supporting the efficacy and short-term safety of DEX in neonates. Reported dosing ranges from 0.5-1.5 mcg/kg/h with or without loading doses. Clinically relevant adverse effects include bradycardia and hypotension. Future studies are needed to determine long-term safety and facilitate clinical applicability.
Pharmacological analysis of dexmedetomidine hydrochloride in pediatric anesthesia during magnetic resonance imaging. [2019]Dexmendetomidine hydrochloride (DEX) is a new common adrenergic receptor agonist, which not only keeps children calm but also has analgesic effect. Dexmedetomidine hydrochloride will enable children to maintain the natural non-REM sleep, which can be stimulated sedation or language arousal. The aim of this study is to observe the sedative effect and adverse drug reactions of dexmedetomidine hydrochloride injection and propofol injection in MRI examination. In this study, no children in the experimental group were required to add sedative drugs, and 2 cases in the control group were treated with sedative drugs. In experimental group, it used dexmedetomidine hydrochloride as (1.64±0.91) g/kg; in control group, dosage of narcotic drugs as (5.26±1.82) g/kg, and the total complication rate of the children in the experimental group was lower than that of the control group (P
Severe form of type 2 reaction in patients of Hansen's disease after withdrawal of thalidomide: case reports. [2013]Thalidomide, a racemic glutamic acid analogue, was first developed in 1954 and subsequently marketed in Europe, Australia and Canada as a sedative and anti-emetic. It was approved by the Food and Drug Administration (FDA) in the USA in 1998 for the treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and suppression of the cutaneous manifestations of ENL recurrences. It is a good choice for management in patients who are dependent on corticosteroids. Common side effects of thalidomide are teratogenicity, peripheral neuropathy, sedation and constipation. We report 4 cases of Hansen's disease with recurrent ENL who were adequately managed on thalidomide. On sudden withdrawal of thalidomide, they relapsed with severe type 2 reaction including necrotic ENL.
Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. [2021]Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ~10 000 children with birth defects resulted in the withdrawal of thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid-1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of thalidomide in Brazil, cases of thalidomide embryopathy have continued to be reported. Here, we present two new cases of thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy.
Rationale use of Thalidomide in erythema nodosum leprosum - A non-systematic critical analysis of published case reports. [2020]Thalidomide is an anti- tumor necrosis factor alpha (TNF-a) drug used mainly in the management of moderate to severe form of Erythema Nodosum Leprosum (ENL). Because of its teratogenic potential it has to be used under proper supervision. Our critical analysis tries to look into the rationale with which it has been used by means of case reports on lepra reaction.
Combined effects of prenatal inhibition of vasculogenesis and neurogenesis on rat brain development. [2018]Malformations of cortical development (MCD) are one of the most common causes of neurological disabilities including autism and epilepsy. To disrupt cortical formation, methylazoxymethanol (MAM) or thalidomide (THAL) has been used to affect neurogenesis or vasculogenesis. Although previous models of MCD have been useful, these models primarily attack a single aspect of cortical development. We hypothesized that simultaneous prenatal exposure to MAM or THAL will lead to the development of a novel and specific type of brain maldevelopment. Rats were prenatally exposed to MAM and THAL. At early postnatal days, brains displayed abnormal ventricular size and hemispheric asymmetry due to altered brain water homeostasis. The postnatal brain was also characterized by gliosis in regions of focal leakage of the blood brain barrier. These morphological abnormalities gradually disappeared at adult stages. Although the adult MAM-THAL rats showed normal cortical morphology, abnormal hippocampal connectivity and mossy fiber sprouting persisted well into adulthood.
N-Adamantyl Phthalimidine: A New Thalidomide-like Drug That Lacks Cereblon Binding and Mitigates Neuronal and Synaptic Loss, Neuroinflammation, and Behavioral Deficits in Traumatic Brain Injury and LPS Challenge. [2022]Neuroinflammation contributes to delayed secondary cell death following traumatic brain injury (TBI), has the potential to chronically exacerbate the initial insult, and represents a therapeutic target that has largely failed to translate into human efficacy. Thalidomide-like drugs have effectively mitigated neuroinflammation across cellular and animal models of TBI and neurodegeneration but are complicated by adverse actions in humans. We hence developed N-adamantyl phthalimidine (NAP) as a new thalidomide-like drug to mitigate inflammation without binding to cereblon, a key target associated with the antiproliferative, antiangiogenic, and teratogenic actions seen in this drug class. We utilized a phenotypic drug discovery approach that employed multiple cellular and animal models and ultimately examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) TBI in mice. NAP mitigated LPS-induced inflammation across cellular and rodent models and reduced oligomeric α-synuclein and amyloid-β mediated inflammation. Following CCI TBI, NAP mitigated neuronal and synaptic loss, neuroinflammation, and behavioral deficits, and is unencumbered by cereblon binding, a key protein underpinning the teratogenic and adverse actions of thalidomide-like drugs in humans. In summary, NAP represents a new class of thalidomide-like drugs with anti-inflammatory actions for promising efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.