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

Study Overview
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Brief Summary
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Very preterm infants are prone to numerous medical complications with lifelong impact. Amongst the most serious are severe 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.

Official Title
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Safety of Combined Therapy With Erythropoietin and Melatonin for Very Preterm Infants With Intraventricular Hemorrhage (SCEMPI)

Conditions
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Intraventricular Hemorrhage of Prematurity

Intervention / Treatment
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* Combination Product: MLT+EPO
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonatal Intensive Care Unit (NICU) inpatients born at >22 and <32 wks gestation (born after 22w6d and before or on 31-6/7 wk GA) sIVH within the first 21 days from birth, defined as at least unilateral grade III5 on head ultrasound performed within the past 5 days expected to survive at least 3 days absence of a congenital anomaly of metabolic or genetic disorder with expected survival less than term equivalent approval of the primary neonatologist arterial or venous access appropriate caregiver to provide informed consent Exclusion Criteria: life expectancy <3 days for any reason severe congenital anomaly or genetic disorder with life expectancy <40 w post-menstrual age (PMA) liver failure severe hematologic crisis such as disseminated intravascular coagulation hydrops fetalis polycythemia (hematocrit < 65%) hypertension for age requiring medication clinical concern or diagnosis of toxoplasmosis, cytomegalovirus, rubella or syphilis infection no appropriate person available or willing to provide informed consent

Ages Eligible for Study
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Minimum Age: 12 Hours
Maximum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLT+EPO<br>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. | Combination Product: MLT+EPO<br>* Melatonin component will be a single daily dose of 30 mg/kg enteral administered in the evening. EPO component is a two-stage regimen with high dose EPO (1000 U/kg/dose q 48 hrs ± 2hr IV) for 10 doses followed by maintenance dose EPO (400 U/kg/dose q Monday, Wednesday, Friday IV/SC) to 33-6/7wk. Maintenance EPO dosing will begin on the day closest to completing the high dose series.<br>|
| Placebo Comparator: Placebo<br>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. | Other: Placebo<br>* Placebo enteral and IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of SAE/DLT including death | 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 | 4 weeks after the conclusion of treatment, up to 38 weeks gestational age | 

Secondary Outcome Measures

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