Melatonin for Neonatal Hypoxic-Ischemic Encephalopathy

Recruiting at 1 trial location

Overseen By Shaveka Gaskins, MBBS, Bsc

Age: < 18

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Florida

Disqualifiers: Metabolism errors, Meningitis, Congenital anomalies, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 3 days

70 Participants Needed

Trial Summary

What is the purpose of this trial?

Hypoxic-Ischemic Encephalopathy (HIE) occurs in 20 per 1000 births. Only 47% of neonates treated with the state of the art therapy (induced systemic hypothermia) have normal outcomes. Therefore, other promising therapies that potentially work in synergy with hypothermia to improve neurologic outcomes need to be tested. One potential agent is melatonin. Melatonin is a naturally occurring substance produced mainly from the pineal gland. Melatonin is widely known for its role in regulating the circadian rhythm, but it has many other effects that may benefit infants with HI injury. Melatonin serves as a free radical scavenger, decreases inflammatory cytokines, and stimulates anti-oxidant enzymes. Therefore, melatonin may interrupt several key components in the pathophysiology of HIE, in turn minimizing cell death and improving outcomes. The research study will evaluate the neuroprotective properties and appropriate dose of Melatonin to give to infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the drug melatonin for treating neonatal hypoxic-ischemic encephalopathy?

Research shows that melatonin has neuroprotective properties, such as reducing inflammation and preventing cell death, which can help protect newborn brains from damage caused by lack of oxygen. Studies in animals and some early human trials suggest melatonin is safe and may improve outcomes for infants with this condition. ^{1 2 3 4 5}

Is melatonin safe for use in humans, particularly for neonatal brain protection?

Melatonin appears to be safe for use in humans, with studies suggesting it is beneficial in protecting newborn brains from injury and has been used safely in children with sleep problems. ^{5 6 7 8 9}

How is the drug melatonin unique in treating neonatal hypoxic-ischemic encephalopathy?

Melatonin is unique because it can cross all physiological barriers to reach subcellular compartments, offering neuroprotection through its antioxidant, anti-apoptotic (preventing cell death), and anti-inflammatory actions. It is considered safe and effective, but more large-scale human trials are needed to confirm its benefits in treating neonatal hypoxic-ischemic encephalopathy. ^{1 2 5 8 10}

Research Team

Michael Weiss

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for newborns over 36 weeks gestation with Hypoxic-Ischemic Encephalopathy (HIE). They must have had an acute event at birth, show signs of brain dysfunction early on, and meet specific blood criteria. Infants already receiving cooling therapy within 6 hours of birth are eligible. Those with suspected meningitis, metabolic disorders, severe hypoglycemia, or significant congenital issues cannot participate.

Inclusion Criteria

The pH level in the cord or newborn baby's blood is less than 7.0.

My newborn had a low Apgar score or needed help breathing after birth.

My newborn was cooled within 6 hours of birth.

Exclusion Criteria

I was born with abdominal issues and other birth defects or genetic conditions.

I show signs of meningitis during a sepsis check.

I have high ammonia levels and low blood sugar.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive melatonin in a dose-escalation study alongside therapeutic hypothermia

3 days

Daily monitoring for 3 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including developmental follow-up at 18-22 months

18-22 months

Long-term safety and efficacy assessment

Evaluation of long-term safety and potential efficacy via developmental follow-up and MRI

18-22 months

Treatment Details

Interventions

• Magnetic Resonance Imaging
• Melatonin
• Neurological Outcome Assessment
• Pharmacokinetics

Trial Overview The study tests melatonin's ability to protect the brain in combination with induced hypothermia in infants suffering from HIE. It aims to find the right dose of melatonin that could help minimize brain cell death by acting as a free radical scavenger and reducing inflammation.

Participant Groups

Group I: Participants 21-30 Experimental Treatment 4 Interventions

This group will receive Melatonin dose of 5 mg/kg enterally, only if the group Participants 11-20 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Group II: Participants 11-20 Experimental Treatment 4 Interventions

This group will the Melatonin dose of 3 mg/kg enteral, only if the group Participants 1-10 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Group III: Participants 1-10 Experimental Treatment 4 Interventions

This group will receive a 0.5 mg/kg enteral dose of Melatonin. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Melatonin is already approved in European Union, United States for the following indications:

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Thrasher Research Fund

Collaborator

Trials

135

Recruited

96,600+

Findings from Research

In a randomized controlled trial involving 80 newborns with hypoxic ischaemic encephalopathy, the addition of melatonin as adjunct therapy significantly improved survival rates, with 87% of the melatonin group surviving compared to 65% in the standard treatment group (p=0.03).

The study suggests that melatonin, administered at a dose of 10mg orally via nasogastric tube within 12 hours of birth, can be an effective treatment to enhance outcomes in newborns suffering from this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial. Ahmad, QM., Chishti, AL., Waseem, N.[2019]

In a study of 45 newborns, including 30 with hypoxic-ischemic encephalopathy (HIE), the combination of melatonin and hypothermia showed significant benefits, including fewer seizures and less white matter abnormalities on MRI compared to hypothermia alone.

The melatonin/hypothermia group demonstrated improved survival rates without neurological or developmental issues at 6 months, suggesting that early melatonin administration may help protect the brain in asphyxiated neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. Aly, H., Elmahdy, H., El-Dib, M., et al.[2022]

Melatonin shows promising neuroprotective properties, including antioxidant and anti-inflammatory effects, which could improve outcomes for infants with neonatal encephalopathy, especially when used alongside therapeutic hypothermia.

In studies using neonatal piglets, the effectiveness of melatonin is time-critical and dose-dependent, with optimal therapeutic levels needing to be reached within the first 2-3 hours after birth for the best results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin for Neonatal Encephalopathy: From Bench to Bedside. Pang, R., Advic-Belltheus, A., Meehan, C., et al.[2022]

Melatonin shows promise as a treatment for neonatal hypoxic-ischemic encephalopathy (HIE) due to its ability to penetrate the blood-brain barrier and its anti-oxidative and anti-inflammatory properties, making it a potential adjunct to therapeutic hypothermia.

The combination of melatonin with therapeutic hypothermia may enhance treatment outcomes for HIE, leveraging melatonin's safety profile and its mechanisms that inhibit cell death and regulate organelle function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy]. Liu, YX., Xia, SW.[2023]

Melatonin shows promise as a neuroprotective agent for infants suffering from perinatal hypoxic-ischemic encephalopathy (HIE), potentially reducing severe long-term neurological issues such as cerebral palsy and epilepsy.

The drug is noted for its safety and ability to penetrate physiological barriers, but further large-scale randomized controlled trials in humans are necessary to confirm its efficacy and establish it as a standard treatment for HIE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin in the management of perinatal hypoxic-ischemic encephalopathy: light at the end of the tunnel? Hendaus, MA., Jomha, FA., Alhammadi, AH.[2020]

In a 26-week study involving 99 children aged 6 to 15 with neurodevelopmental disorders, melatonin significantly reduced sleep onset latency by an average of 36.7 minutes, showing sustained effects even after treatment ended.

Melatonin treatment also led to improvements in temper upon waking and reduced sleepiness after awakening, with no significant adverse events reported after 16 weeks, indicating it is a safe long-term option for managing sleep problems in these children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders. Yuge, K., Nagamitsu, S., Ishikawa, Y., et al.[2022]

In a 12-week trial involving 146 children with neurodevelopmental disorders, melatonin significantly reduced the time it took for children to fall asleep by an average of 37.5 minutes, while also increasing total sleep time by about 22.4 minutes according to parent-reported diaries.

While melatonin improved sleep onset, it resulted in earlier waking times and did not lead to significant improvements in child behavior or family functioning, indicating that while it is safe and tolerable, its overall impact on sleep quality may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. Gringras, P., Gamble, C., Jones, AP., et al.[2022]

Melatonin shows promise as a neuroprotective agent for preventing brain injury in preterm infants and those affected by neonatal asphyxia, due to its antioxidant and neuromodulatory properties.

Current research, including preclinical studies and some clinical trials, supports the potential benefits of melatonin in protecting newborns' brains, although more extensive clinical data is still needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and the newborn brain. Colella, M., Biran, V., Baud, O.[2017]

In a preliminary study involving 11 severely disabled children and young adults, ramelteon was effective in improving sleep for 8 out of the 11 participants after they had previously been treated with melatonin.

Ramelteon was generally well-tolerated, with only mild daytime sleepiness reported in three patients, suggesting it may be a safe option for managing sleep disturbances in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with ramelteon for sleep disturbance in severely disabled children and young adults]. Miyamoto, A., Fukuda, I., Tanaka, H., et al.[2018]

Melatonin shows promise as a neuroprotective agent for neonatal encephalopathy (NE) based on pre-clinical studies, but clinical evidence is limited, with only five randomized controlled trials involving 215 neonates reviewed.

The combination of melatonin with therapeutic hypothermia did not significantly reduce mortality compared to hypothermia alone, indicating that more robust clinical trials are needed to clarify its effectiveness in improving neurodevelopmental outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials. Ahmed, J., Pullattayil S, AK., Robertson, NJ., et al.[2021]

References

1. Pakistan pubmed.ncbi.nlm.nih.gov

Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial. [2019]

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

Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Melatonin for Neonatal Encephalopathy: From Bench to Bedside. [2022]

4. China pubmed.ncbi.nlm.nih.gov

[Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy]. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Melatonin in the management of perinatal hypoxic-ischemic encephalopathy: light at the end of the tunnel? [2020]

6. England pubmed.ncbi.nlm.nih.gov

Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. [2022]

8. Ireland pubmed.ncbi.nlm.nih.gov

Melatonin and the newborn brain. [2017]

9. Japan pubmed.ncbi.nlm.nih.gov

[Treatment with ramelteon for sleep disturbance in severely disabled children and young adults]. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials. [2021]