Safety of Erythropoietin and Melatonin for Very Preterm Infants With Intraventricular Hemorrhage (SCEMPI)

Johns Hopkins University

Status and phase: Enrolling; Phase 1

Conditions: Intraventricular Hemorrhage of Prematurity

Treatments: Combination Product: MLT+EPO; Other: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05617833

R01HD104673-01A1 (U.S. NIH Grant/Contract)

IRB00301237

Details and patient eligibility

About

Very preterm infants are prone to numerous medical complications with lifelong impact. Amongst the most serious neurologically are white matter injury (WMI), intraventricular hemorrhage (IVH) and the subsequent progression to posthemorrhagic hydrocephalus (PHH). Currently, the only treatment for PHH is surgery, most commonly with shunts that are prone to malfunction across the lifespan. Preclinical data show that melatonin (MLT) and erythropoietin (EPO), when administered in a sustained dosing regimen, may promote neuro-repair, including the progression from early postnatal IVH to subsequent PHH. The investigators will perform a Phase I, single institution, randomized, double-blind trial for very preterm infants with IVH and WMI to define a safe combination dose of MLT and EPO. A maximum of 60 very preterm neonates with IVH and/or moderate to severe WMI will be enrolled, treated through 33w6/7d, and followed to 37w6/7d. Neonates will be randomized 3:1 between MLT+EPO and placebo, with all receiving standard of care. The primary endpoint is a composite serious adverse event (SAE)/dose limiting toxicity (DLT). The investigators hypothesize that the MLT+EPO SAE/DLT rate will not be higher than the placebo rate. Secondary outcomes will be rate of co-morbidities of preterm birth. Exploratory data, collected to guide design of future clinical trials for efficacy, will include serial neuro-imaging metrics acquired from clinical images, serial neonatal neurodevelopmental examinations, serum and urine MLT and EPO levels, liquid and gut microbiome biomarkers. Successful implementation of this initial safety trial will provide essential data to guide the next stage of clinical trials to test if sustained MLT+EPO treatment can reduce neurological deficits, including the need for surgical intervention and the lifelong burden of shunted hydrocephalus.

Enrollment: 60 estimated patients

Sex: All

Ages: 12 hours to 2 months old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Neonatal intensive care unit (NICU) inpatients born at >22 and <32 weeks gestation (born after 22w-6/7 and before or on 31-6/7 week GA)
• IVH or moderate/severe white matter injury within the first 21 days from birth
• Infants born prior to 30 weeks GA may enroll until DOL 30. Infants born after 30 weeks may enroll until DOL 21. Treatment must be started by 33+0.
• Approval of the primary neonatologist
• Appropriate caregiver to provide informed consent
• Is not known to meet or suspected of meeting any of the exclusion criteria (below).

Exclusion criteria

• Participation in another pharmacological intervention trial that involves multiple doses of a medication that may interact with EPO+MLT. Examples of exemptions would include single dose administration for pharmacokinetic studies of an antibiotic, a single or few doses of a new surfactant, or a single intervention to reduce pain.
• Is on jet ventilator or has not been off jet ventilator for at least 72 hours
• Has been diagnosed with or is suspected of having a congenital anomaly or genetic disorder associated with brain malformation or life expectancy <40 weeks post menstrual age (PMA). These include but are not limited to TORCH infections associated with radiographic evidence of substantial brain injury, trisomy 13, coarctation of the aorta, and severe liver failure. TORCH infections not associated with radiographic evidence of brain malformation or treatment for presumed TORCH infection are not exclusionary.
• Is within 3 days of starting treatment for a severe clinical condition which is potentially associated with a life expectancy <3 days. These include but are not limited to disseminated intravascular coagulation (DIC)/severe hematologic crisis, severe sepsis, Hypoxic-ischemic encephalopathy (HIE), severe brain injury
• Other clinical conditions including:

Hydrops fetalis Hypertension for age requiring sustained medication Polycythemia (hematocrit >65%)

- No caregiver to provide consent

The clinical condition of potential candidates will be monitored throughout the eligibility period to ensure the participant's continued candidacy for participating in the trial.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 2 patient groups, including a placebo group

MLT+EPO

Experimental group

Description:

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.

Treatment:

Combination Product: MLT+EPO

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Other: Placebo