Melatonin + Erythropoietin for Intraventricular Hemorrhage

(SCEMPI Trial)

Overseen By Kathryn Lowe

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Johns Hopkins University

Disqualifiers: Congenital anomaly, Genetic disorder, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 4 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find a safe dose of melatonin and erythropoietin for very premature babies with a serious brain bleed called intraventricular hemorrhage (sIVH). Researchers believe this combination might prevent the condition from worsening, which often requires surgery. Babies born very early, between 22 and 32 weeks, and who have had sIVH within their first 21 days are good candidates for this trial. The goal is to see if these treatments can help reduce the need for surgery and improve long-term outcomes. Participants will receive either the treatment or a placebo, along with standard care, to compare safety and effects.

As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if participants must stop taking their current medications. However, since the trial involves very preterm infants, any medication changes would likely be managed by the medical team in the NICU.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that melatonin (MLT) and erythropoietin (EPO) might be safe for premature babies. Early studies suggest these treatments can help prevent brain bleeding in babies without causing harm. Researchers are investigating whether administering high doses of MLT and EPO over several weeks is safe for these infants. The primary goal is to ensure this combination does not cause more serious side effects than a placebo (a treatment with no active ingredients). As this study is in its early stages, it focuses on understanding safety, indicating that more remains to be learned about how infants respond to these treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for intraventricular hemorrhage, which typically focus on managing symptoms and preventing further bleeding, the combination of Melatonin and Erythropoietin (MLT+EPO) offers a unique approach. Melatonin, known for its antioxidant properties, may help protect brain cells from damage, while Erythropoietin, originally used to stimulate red blood cell production, might reduce inflammation and promote brain repair. This dual-action strategy aims not only to prevent further injury but also to enhance recovery, potentially providing a more comprehensive treatment option. Researchers are excited about this approach because it targets both neuroprotection and neuroregeneration, offering hope for improved outcomes in patients.

What evidence suggests that MLT+EPO might be an effective treatment for intraventricular hemorrhage?

This trial will evaluate the combination of melatonin (MLT) and erythropoietin (EPO) to prevent serious brain problems in very premature babies. Research has shown that using MLT and EPO together might help prevent early brain bleeding from worsening and requiring surgery. This is crucial because the usual treatment often involves surgery, which can lead to lifelong issues. Initial results suggest that this treatment could offer a safer, non-surgical approach to managing these brain problems. Although still under investigation in this trial, the early results are promising and warrant further research. Participants in this trial will receive either the MLT+EPO combination or a placebo. ^{1 2 3 4 5}

Who Is on the Research Team?

Shenandoah Robinson, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for very preterm infants born between 22+6/7 and 31+6/7 weeks of gestation, who have severe intraventricular hemorrhage (sIVH) diagnosed within the first 21 days. They must be expected to survive at least three more days, not have a life-threatening congenital anomaly or disorder, and have a caregiver able to consent.

Inclusion Criteria

My baby had a severe brain bleed within 21 days after birth.

My baby was born between 23 and 32 weeks of pregnancy and is in the NICU.

You are expected to live for at least 3 more days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MLT and EPO or placebo until 33 weeks and 6 days gestational age

Approximately 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• MLT+EPO

Trial Overview

The trial tests if melatonin (MLT) combined with erythropoietin (EPO) can safely prevent progression from sIVH to posthemorrhagic hydrocephalus in preterm infants. It's a randomized, double-blind study comparing MLT+EPO against placebo, alongside standard care.

How Is the Trial Designed?

Group I: MLT+EPO Experimental Treatment 1 Intervention

Melatonin 3 mg/mL oral syringe enterally every evening. Dose will be divided in half and administered at evening cares. High dose epoetin alfa epbx recombinant (1000 units/kg) syringe subcutaneously or intravenously every 48 hours for 10 doses. Low dose epoetin alfa-epbx recombinant (400 units/kg) subcutaneously or intravenously three times weekly on Monday, Wednesday, and Friday until age 33-6/7wk.

Group II: Placebo Placebo Group 1 Intervention

Placebo oral syringe enterally every evening. Placebo syringe IV every 48 hours for 10 doses. Placebo subcutaneously or intravenously three times weekly on Monday, Wednesday, and Friday until age 33-6/7wk.

MLT+EPO is already approved in United States, European Union for the following indications:

Approved in United States as Epoetin alfa for:

• Anemia
• Anemia Due to Chronic Kidney Disease
• Anemia Prior to Surgery
• Anemia, Chemotherapy Induced
• Anemia, Drug Induced

Approved in European Union as Epoetin alfa for:

• Anemia
• Anemia Due to Chronic Kidney Disease
• Anemia Prior to Surgery
• Anemia, Chemotherapy Induced
• Anemia, Drug Induced

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

In a study involving 49 male piglets, both melatonin and erythropoietin were found to be safe and effective adjunct therapies to therapeutic hypothermia, leading to faster recovery of brain activity as measured by EEG and improved cellular outcomes in the brain.

Melatonin specifically reduced cell death in the sensorimotor cortex and improved metabolic markers, while erythropoietin promoted oligodendrocyte survival, indicating that these therapies have distinct neuroprotective mechanisms that could be optimized with timing and combination strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia. Pang, R., Avdic-Belltheus, A., Meehan, C., et al.[2021]

In a study of 116 preterm infants, elevated levels of erythropoietin (EPO) in umbilical cord blood were found to be a significant predictor of the risk for developing intraventricular hemorrhage (IVH), independent of gestational age.

The study found a direct relationship between cord blood EPO and interleukin-6 (IL-6) levels, but only EPO levels were independently associated with IVH risk, suggesting that monitoring EPO could help identify at-risk newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood erythropoietin and interleukin-6 for prediction of intraventricular hemorrhage in the preterm neonate. Bhandari, V., Buhimschi, CS., Han, CS., et al.[2021]

Erythropoietin (EPO) treatment in a preclinical model of germinal matrix-intraventricular hemorrhage (GM-IVH) significantly reduced brain atrophy and ventricle enlargement, indicating its potential neuroprotective effects.

EPO also improved neuronal density, reduced inflammation, and preserved learning and memory abilities, suggesting it could be a promising therapeutic approach for preventing long-term neurodevelopmental issues in preterm infants affected by GM-IVH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage. Hierro-Bujalance, C., Infante-Garcia, C., Sanchez-Sotano, D., et al.[2020]

In a study involving 117 patients with severe intracerebral hemorrhage (ICH), non-survivors had significantly higher serum melatonin levels compared to survivors during the first week after diagnosis, indicating a potential link between melatonin levels and patient outcomes.

Serum melatonin concentrations measured within the first 7 days of ICH were found to be strong predictors of 30-day mortality, with a high area under the curve (AUC) for mortality prediction, suggesting that melatonin levels could be useful in clinical assessments of patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mortality prediction by serum melatonin levels of patients with spontaneous intracerebral hemorrhage. Lorente, L., Martín, MM., Abreu-González, P., et al.[2022]

In a preclinical model of posthemorrhagic hydrocephalus of prematurity (PHHP) involving preterm rats, a combination of erythropoietin (EPO) and melatonin (MLT) treatment significantly prevented the development of macrocephaly and ventriculomegaly, which are key features of PHHP.

The EPO+MLT treatment not only improved neurodevelopmental outcomes, as shown by better performance in cliff aversion tests, but also normalized structural brain integrity, suggesting it could be a promising non-surgical intervention for preventing PHHP in vulnerable preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats. Robinson, S., Conteh, FS., Oppong, AY., et al.[2020]

In a study of 210 women who delivered vaginally, different postpartum oxytocin administration routes (intramuscular, intravenous, or a combination) did not significantly affect the decline in hemoglobin (Hb) and hematocrit (Hct) levels after delivery.

Overall, the decline in Hb and Hct was minor across all groups, indicating that the choice of oxytocin regimen may not impact maternal hematological outcomes following vaginal birth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Route of postpartum oxytocin administration and maternal hemoglobin decline - A randomized controlled trial. Ashwal, E., Amikam, U., Wertheimer, A., et al.[2022]

In a phase 1 study involving 31 participants, the safety profiles of inhaled (IH) oxytocin and intramuscular (IM) oxytocin were found to be similar, with no deaths reported and a comparable number of adverse events.

The pharmacokinetics (PK) of both IH and IM oxytocin could not be clearly established in women during the third stage of labor, as most plasma oxytocin concentrations were below quantification limits after administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study. Gajewska-Knapik, K., Kumar, S., Sutton-Cole, A., et al.[2023]

In a study involving 64 women with primary postpartum hemorrhage, 800 mcg of misoprostol administered rectally was found to be more effective than the combination of Syntometrine and Syntocinon in stopping hemorrhage within 20 minutes.

The results showed a significant 28.1% improvement in hemorrhage control with misoprostol (p=0.01), highlighting its potential as a safe and effective treatment option for postpartum hemorrhage, especially in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized study comparing rectally administered misoprostol versus Syntometrine combined with an oxytocin infusion for the cessation of primary post partum hemorrhage. Lokugamage, AU., Sullivan, KR., Niculescu, I., et al.[2019]

In a study of 300 women, administering 600 micrograms of sublingual misoprostol resulted in the lowest blood loss during the third stage of labor compared to 400 micrograms of misoprostol, intravenous oxytocin, and intravenous methylergometrine.

The use of 600 micrograms of misoprostol also led to the shortest duration of the third stage of labor, while methylergometrine was associated with higher blood pressure as an adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of sublingual misoprostol, intravenous oxytocin, and intravenous methylergometrine in active management of the third stage of labor. Singh, G., Radhakrishnan, G., Guleria, K.[2022]

Melatonin (ML) administration after intracerebral hemorrhage (ICH) significantly improved motor function in rat models, indicating its potential as a neuroprotective treatment.

The mechanism of ML's protective effect involves reducing oxidative stress in oligodendrocytes and astrocytes, leading to enhanced neuronal responsiveness in areas of the brain remote from the injury site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration after a small hemorrhage near the internal capsule in rats. Ueda, Y., Masuda, T., Ishida, A., et al.[2022]

In a study of 686 women, both intramuscular syntometrine and intravenous syntocinon were found to be equally effective in preventing postpartum hemorrhage, showing no significant difference in mean blood loss.

However, the use of intramuscular syntometrine was associated with a higher incidence of elevated diastolic blood pressure (>90 mmHg) 30 minutes after delivery, indicating a potential safety concern compared to intravenous syntocinon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised controlled trial comparing the efficacy of intramuscular syntometrine and intravenous syntocinon, in preventing postpartum haemorrhage. Rashid, M., Clark, A., Rashid, MH.[2013]

Melatonin (MLT) is a safe neuroprotective agent that can reduce brain injury and improve brain development in preterm fetal sheep after an acute hypoxic ischemic insult, as shown in a study involving 15 fetal sheep.

MLT administration after hypoxia decreased cell death, inflammation, and oxidative stress in the white matter, leading to increased oligodendrocyte numbers and improved myelin density, although its benefits were specific to certain brain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Beneficial Effects of Melatonin Administration Following Hypoxia-Ischemia in Preterm Fetal Sheep. Yawno, T., Mahen, M., Li, J., et al.[2020]

Both single-dose immediate treatment (SDIT) and 7-day continuous treatment (7DCT) with melatonin improved long-term behavior and reduced white matter damage in neonatal rats with hypoxic-ischemic brain damage (HIBD).

The 7DCT regimen was found to be more effective than SDIT, showing better results in spatial learning and memory, as well as higher expression of neuronal markers and myelin proteins, indicating enhanced neuronal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of different melatonin treatment regimens on white matter damage in neonatal rats with hypoxic-ischemic brain damage]. Ma, R., Ma, YH., Zhang, XY., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05617833

Safety of Erythropoietin and Melatonin for Very Preterm ...

Preclinical data show that melatonin (MLT) and erythropoietin (EPO), when administered in a sustained dosing regimen, can prevent the hallmarks of ...

2.

hopkinsmedicine.org

hopkinsmedicine.org/neurology-neurosurgery/specialty-areas/pediatric-neurosurgery/infant-brain-bleed-clinical-trial

Erythropoietin and Melatonin for Very Preterm Infants with ...

This research study is to learn whether preterm babies can safely tolerate high doses of melatonin and EPO when given over several weeks.

3.

reporter.nih.gov

reporter.nih.gov/search/14E9CE024F8FC5D27598B8961CAA4A01A2FFCEB861BF/project-details/10845516

Project Details - NIH RePORTER

Preclinical data show that melatonin (MLT) and erythropoietin (EPO), when administered in a sustained dosing regimen, can prevent the hallmarks of ...

4.

trialx.com

trialx.com/clinical-trials/listings/257784/safety-of-erythropoietin-and-melatonin-for-very-preterm-infants-with-intraventricular-hemorrhage/

Safety of Erythropoietin and Melatonin for Very Preterm ...

Preclinical data show that melatonin (MLT) and erythropoietin (EPO), when administered in a sustained dosing regimen, can prevent the ...

5.

frontiersin.org

frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2018.00322/full

Extended Combined Neonatal Treatment With ...

Neonatal systemic EPO+MLT treatment prevented multiple hallmarks of PHHP, consistent with a clinically viable, non-surgical treatment strategy.