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

Phase 1

Recruiting

• Conditions: Intraventricular Hemorrhage of Prematurity
• Interventions: Other: Placebo; Combination Product: MLT+EPO

• Registration Number: NCT05617833
• Lead Sponsor: Johns Hopkins University

Brief Summary

Very preterm infants are prone to numerous medical complications with lifelong impact. Amongst the most serious are significant intraventricular hemorrhage (sIVH) 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, can prevent the hallmarks of progression from early postnatal sIVH to subsequent PHH. The investigators will perform a Phase I, single institution, randomized, double-blind trial for very preterm infants with sIVH to define a safe combination dose of MLT and EPO. A maximum of 60 very preterm neonates with sIVH 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, and liquid 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 the need for surgical intervention, and avoid the lifelong burden of shunted hydrocephalus.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-11-08
• Study First Submitted QC: 2022-11-08
• Study First Posted: 2022-11-16
• Study Start: 2024-04-30
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-06
• Last Update Posted: 2025-05-07
• Primary Completion: 2027-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. 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)
2. sIVH within the first 21 days from birth, defined as at least unilateral grade II on head ultrasound (HUS) performed within 18 days of enrollment
3. Approval of the primary neonatologist
4. Appropriate caregiver to provide informed consent
5. Is not known to meet or suspected of meeting any of the exclusion criteria (below).

Exclusion Criteria

1. 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.

2. Is on jet ventilator or has not been off jet ventilator for at least 72 hours

3. 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.

4. 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

5. Other clinical conditions including:

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

6. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	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	MLT+EPO	Melatonin 3 mg/mL oral syringe enterally every evening. For neonates weighing less than 1200 g, divide the dose in half and administer each half 30 minutes apart. High dose epoetin alfa epbx recombinant (1000 units/kg) syringe IV 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.

Primary Outcome Measures

Name	Time	Method
Rate of SAE/DLT including death	4 weeks after the conclusion of treatment, up to 38 weeks gestational age	to test the hypothesis that rate of Serious Adverse Events (SAE)/dose limiting toxicity (DLT) with a cocktail of MLT and EPO in very preterm infants with severe intraventricular hemorrhage (sIVH) will have similar rate of SAE/DLT in subjects treated with placebo

Secondary Outcome Measures

Name	Time	Method
Efficacy of EPO plus MLT as assessed by rate of preterm birth related co-morbidities	4 weeks after the conclusion of treatment, up to 38 weeks gestational age	Determine whether treatment with EPO plus MLT alters the rate of preterm birth related co-morbidities compared to concurrent placebo controls.

Trial Locations

Locations (1)

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States