Sepsis is a very important cause of death in preterm infants. Survival from sepsis is often related to severe short and long term morbidity. Despite optimal antibiotic treatment, immaturity of the immune system in preterm newborns causes this severe sepsis related mortality and morbidity.
We now propose to study if preterm newborns with sepsis could benefit, next to antibiotics, from treatment with pentoxifylline (PTX), which is registered for adults with intermittent claudication. PTX has already been shown to have multiple in vitro and in vivo effects that could help to recover from sepsis. Immunomodulation of PTX seems most effective in preterm newborns. PTX is off patent and inexpensive. The health gain could be enormous.
We want to determine how and in what optimal dose PTX should be used in preterm infants suffering from sepsis. Previous clinical studies have already indicated the safety of the drug in preterm infants. High quality studies to determine the optimal dose and if PTX should be registered for this indication is missing.
Our project contains 2 studies in preterm infants.
In part A we will perform a dose finding study in infants with sepsis and increased inflammation. In this study we will evaluate different dosages, using a continuous reassessment method, of continuous PTX on the recovery of TNF-alpha, other inflammatory biomarkers and clinical recovery.
In the second study, part B, we will compare the optimal PTX dosage to a placebo infusion in a blinded randomized controlled trial. All preterm newborns with a suspected sepsis will be included if born before 29 weeks. The primary outcome will be a composite outcome, including mortality.
State of the art techniques will be used to determine the exact effects of PTX, including high frequency physiological data, multiple biomarkers and population PK/PD modeling.
In this way we aim to find a new treatment that is ready for implementation to improve neonatal survival and sepsis related morbidity.