Intraventricular Hemorrhage of Prematurity
Conditions
Keywords
SCEMPI, Erythropoietin, Melatonin, preterm infants, Intraventricular Hemorrhage
Brief summary
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.
Interventions
COMBINATION_PRODUCTMLT+EPO
Melatonin component will be a daily dose of 30 mg/kg enteral administered in the evening in a split dose given at cares/feedings. EPO component is a two-stage regimen with high dose EPO (1000 U/kg/dose q 48 hrs ± 2hr subcutaneously or intravenously) for 10 doses followed by maintenance dose EPO (400 U/kg/dose q Monday, Wednesday, Friday subcutaneously or intravenously) to 33-6/7wk. Maintenance EPO dosing will begin on the day closest to completing the high dose series.
OTHERPlacebo
Placebo enteral and IV
Sponsors
Johns Hopkins University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 2 Months
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
CONTACTKathryn Lowe
CONTACTJessica Wollett
STUDY_CHAIRShenandoah Robinson, MD
Johns Hopkins University
Outcome results
None listed