Anakinra Pilot 2 - A Study to Optimise Dose and Route of Administration of Anakinra in Preterm Infants

Population Pharmacokinetics (PopPK) Model of the Clearance of anakinra in extremely premature neonates from birth, during the 3-week treatment period.

Point Estimate of Population Total Clearance (CL) of anakinra will be reported.

Population Pharmacokinetics (PopPK) Model of the Volume of Distribution of anakinra in extremely premature neonates from birth, during the 3-week treatment period.

Point Estimate of Population Volume of Distribution (VD) of anakinra will be reported.

Population Pharmacokinetics (PopPK) Model of the Absorption of Population of subcutaneously administered anakinra in extremely premature neonates from birth, during the 3-week treatment period.

Point Estimate of Population Absorption of subcutaneously administered anakinra will be reported.

Incidence of bronchopulmonary dysplasia

Early efficacy endpoints (exploratory): incidence of bronchopulmonary dysplasia, in comparison to contemporary unit and national statistics.

Hammersmith infant neurological examination

Early efficacy endpoint (exploratory): Hammersmith infant neurological examination; performed at 3-4 months of corrected age, in comparison to contemporary unit and national statistics.

Incidence of intracranial/intraventricular haemorrhage and peri-ventricular leukomalacia.

Early efficacy endpoint (exploratory): incidence of intracranial/intraventricular haemorrhage and peri-ventricular leukomalacia, in comparison to contemporary unit and national statistics.

Safety of anakinra in extremely premature neonates.

Safety of anakinra IV and SC in premature neonates, at 3 dosing levels, measured as incidence of safety endpoints in particular late-onset sepsis and necrotizing enterocolitis (compared with contemporary unit and national statistics) as well as neutropenia, thrombocytopenia, acute kidney injury, drug-induced liver injury (per Hy's Law).

Feasibility of 3 weeks of anakinra administration to extremely premature neonates from birth, both intravenously and subcutaneously.

Feasibility of anakinra IV and SC in premature neonates, at 3 dosing levels, measured as succesful completion of intervention treatment course, including subcutaneous dosing.

Influence of anakinra on microbiome.

Monitoring for lung and gut microbiome changes during the treatment course by collection and analysis of bronchoalveolar lavage fluid (in intubated infants), nasopharyngeal swabs, and stool.

Pharmacokinetic (PK)/Pharmacodynamic (PD) Model of the Effect of anakinra Systemic Exposure on clinical endpoints.

Point Estimate of population IC50 of anakinra associated with a reduction in incidence of early efficacy endpoints (exploratory), including bronchopulmonary dysplasia, intracranial/intraventricular haemorrhage \& peri-ventricular leukomalacia, and Hammersmith infant neurological examination; performed at 3-4 months of corrected age.

Pharmacokinetic (PK)/Pharmacodynamic (PD) Model of the Effect of anakinra Systemic Exposure on biomarkers of the inflammatory cascade.

Point Estimate of population IC50 of anakinra, i.e. the drug concentration required to produce 50% of maximal inhibition of the IL-1-driven inflammatory cascade. Biomarkers investigated will include cellular proteomic biomarkers of inflammatory activity and inhibition, including lymphoid and myeloid cell polarisation and activation as well as responsiveness to stimulants such as lipopolysaccharide (LPS) and PMA/ionomycin during the treatment course.