Dexmedetomidine for Neonatal Encephalopathy

(DICE Trial)

Recruiting at 4 trial locations

Overseen By Mariana Baserga, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Disqualifiers: Chromosomal anomalies, Heart defects, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: First 96 hours of life

50 Participants Needed

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. ^{1 2 3 4 5}

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. ^{1 4 5 6 7}

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. ^{8 9 10 11 12}

Research Team

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.

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
• Morphine Sulfate

Trial Overview The 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

Group I: Dexmedetomidine (DMT) Experimental Treatment 1 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: Morphine Active Control 1 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

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

Dexmedetomidine (DEX) is an effective sedative with neuroprotective properties, showing improved outcomes in ICU patients and potential as a non-opioid analgesic, which is important for reducing opioid-related side effects.

While DEX has significant benefits for the nervous system, clinicians must be aware of potential adverse effects like hypotension and bradycardia, which can be managed with medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects. Bozorgi, H., Zamani, M., Motaghi, E., et al.[2021]

Dexmedetomidine, while effective for sedation in a term infant undergoing artificial ventilation, was associated with the emergence of epileptic seizures and non-epileptic abnormal movements, indicating potential adverse effects in neonates.

The symptoms resolved 12 hours after stopping dexmedetomidine without the need for antiepileptic medication, suggesting that while it can be beneficial, careful monitoring is necessary due to its impact on the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epileptic seizures induced by dexmedetomidine in a neonate. Kubota, T., Fukasawa, T., Kitamura, E., et al.[2013]

Dexmedetomidine was found to be more effective than fentanyl for sedation in mechanically ventilated premature neonates, requiring less additional sedation and resulting in a shorter duration of mechanical ventilation (14.4 days vs. 28.4 days).

The use of dexmedetomidine also led to quicker recovery metrics, such as earlier meconium passage and faster achievement of full enteral feeds, along with a lower incidence of culture-positive sepsis compared to fentanyl.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. O'Mara, K., Gal, P., Wimmer, J., et al.[2022]

In a study of 19 patients aged 65 on average who underwent various cardiac surgeries, continuous infusion of dexmedetomidine was found to effectively sedate patients without significantly affecting heart rate or other hemodynamic parameters, except for a decrease in blood pressure.

Dexmedetomidine caused a reduction in systemic vascular resistance and mixed venous oxygen saturation, indicating its vaso-dilating effects, which suggests it can be safely used as a sedative in the post-operative setting after cardiac surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of dexmedetomidine in patients after cardiac surgery. Ishikawa, S., Kugawa, S., Neya, K., et al.[2006]

Dexmedetomidine may be a safer and more effective alternative to morphine for managing pain and sedation in newborns with hypoxia-ischemia encephalopathy (HIE) undergoing therapeutic hypothermia, as it has neuroprotective properties and does not suppress ventilation.

The ongoing DICE trial, which involves 50 neonates with moderate to severe HIE, aims to assess the safety and pharmacokinetics of dexmedetomidine compared to morphine, potentially paving the way for a larger Phase III trial focused on long-term neurodevelopmental outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial): A Randomized Controlled Trial: Background, Aims and Study Protocol. Baserga, M., DuPont, TL., Ostrander, B., et al.[2022]

Dexmedetomidine has been shown to be effective and generally safe for short-term use in neonates, based on a review of 21 studies and 1 case report.

The recommended dosing for dexmedetomidine in neonates ranges from 0.5 to 1.5 mcg/kg/h, but caution is advised due to potential adverse effects like bradycardia and hypotension, highlighting the need for further research on long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine - An emerging option for sedation in neonatal patients. McDonald, D., Palsgraf, H., Shah, P.[2022]

Dexmedetomidine hydrochloride (DEX) is effective for sedation in children undergoing MRI examinations, showing a lower total complication rate compared to propofol, with no additional sedatives needed in the DEX group.

The study demonstrated that DEX not only maintains natural non-REM sleep but also provides a higher quality of MRI results, making it a promising option for clinical sedation with fewer adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological analysis of dexmedetomidine hydrochloride in pediatric anesthesia during magnetic resonance imaging. Yang, Z., Song, G., Hu, W., et al.[2019]

Thalidomide is an effective treatment for the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL), particularly in patients who rely on corticosteroids, as demonstrated in four reported cases of Hansen's disease.

Withdrawal of thalidomide can lead to severe relapses in patients, highlighting the importance of careful management and monitoring when discontinuing this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe form of type 2 reaction in patients of Hansen's disease after withdrawal of thalidomide: case reports. Rattan, R., Shanker, V., Tegta, GR., et al.[2013]

Thalidomide, originally withdrawn from the market due to causing severe birth defects in approximately 10,000 children, is still associated with cases of thalidomide embryopathy despite strict regulations on its use in Brazil.

The drug has been effectively used since the mid-1990s for treating conditions like leprosy and certain cancers, but ongoing reports of thalidomide embryopathy highlight the need for continued vigilance in its prescription and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. Vianna, FSL., Schüler-Faccini, L., Leite, JCL., et al.[2021]

Thalidomide is effective in managing moderate to severe Erythema Nodosum Leprosum (ENL), but its use must be carefully supervised due to its potential to cause birth defects.

Out of 41 analyzed case reports, there were instances of both proper and improper use of thalidomide, highlighting the importance of following established guidelines, such as using Clofazimine before thalidomide and avoiding its use in cases of neuritis without steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale use of Thalidomide in erythema nodosum leprosum - A non-systematic critical analysis of published case reports. Thangaraju, P., Venkatesan, S., Gurunthalingam, M., et al.[2020]

Prenatal exposure to both methylazoxymethanol (MAM) and thalidomide (THAL) in rats led to significant early postnatal brain abnormalities, including altered ventricular size and hemispheric asymmetry, indicating a disruption in brain development.

While the overall cortical structure appeared normal in adulthood, the rats exhibited lasting issues with hippocampal connectivity and mossy fiber sprouting, suggesting that early malformations can have long-term effects on brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effects of prenatal inhibition of vasculogenesis and neurogenesis on rat brain development. Fan, QY., Ramakrishna, S., Marchi, N., et al.[2018]

N-adamantyl phthalimidine (NAP) is a new drug developed to reduce neuroinflammation after traumatic brain injury (TBI) without the harmful side effects associated with thalidomide, as it does not bind to cereblon, a protein linked to adverse effects.

In mouse models, NAP effectively reduced inflammation, neuronal loss, and behavioral deficits following TBI, suggesting it could be a promising treatment for TBI and possibly for chronic neurodegenerative conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Hsueh, SC., Luo, W., Tweedie, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Epileptic seizures induced by dexmedetomidine in a neonate. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. [2022]

4. Italy pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of dexmedetomidine in patients after cardiac surgery. [2006]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial): A Randomized Controlled Trial: Background, Aims and Study Protocol. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Dexmedetomidine - An emerging option for sedation in neonatal patients. [2022]

7. Pakistan pubmed.ncbi.nlm.nih.gov

Pharmacological analysis of dexmedetomidine hydrochloride in pediatric anesthesia during magnetic resonance imaging. [2019]

8. India pubmed.ncbi.nlm.nih.gov

Severe form of type 2 reaction in patients of Hansen's disease after withdrawal of thalidomide: case reports. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. [2021]

10. Brazil pubmed.ncbi.nlm.nih.gov

Rationale use of Thalidomide in erythema nodosum leprosum - A non-systematic critical analysis of published case reports. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Combined effects of prenatal inhibition of vasculogenesis and neurogenesis on rat brain development. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

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]