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

Advances in neonatal intensive care have significantly improved the survival rates for extremely premature neonates. Despite this, many survivors develop chronic conditions such as cerebral palsy and chronic lung disease, primarily due to the pro-inflammatory environment common in these patients. Efforts to reduce these conditions using anti-inflammatory glucocorticoids are effective but are hindered by significant adverse effects that outweigh potential benefits for most neonates.

Crucially, not only is inflammation an important driver of morbidities of prematurity, but as shown by the investigators and other research groups, the potent pro-inflammatory cytokine interleukin-1 is a key player.

A phase I/IIa trial of anakinra in extremely premature infants (24 - 27+6 weeks gestational age) demonstrated feasibility of administration intravenous over the first 3 weeks of life, without any acute safety concerns and confirmation of mechanistic pharmacokinetic predictions.

The aims of this phase II dose-ranging trial (Anakinra Pilot 2, AP2) are to:

1. Establish pharmacokinetics, linearity and target concentration attainment over a range of doses, to determine optimal dosing regimen. 2. Assess feasibility and pharmacokinetics of an alternative route of administration (RoA), namely subcutaneous, in week 3 of treatment. 3. Further expand safety \& feasibility, as well as perform exploratory pharmacometric dose-exposure-response analysis, against biomarkers and early efficacy endpoints.

The primary outcome is to refine understanding of anakinra population pharmacokinetics in extremely premature neonates, and at 3 different dosing levels, to allow determination of optimal dose for population target concentration attainment in future trials.

In addition, the pharmacokinetics of subcutaneously administered anakinra in extremely premature neonates (from week 3) will be explored. Population pharmacokinetic model development and validation, for intravenous and subcutaneous anakinra in premature neonates over the first 3 weeks of life, to enable dose determination for target concentration attainment.

Model performance and validation will be based on metrics and graphics of model 'goodness-of-fit', precision of parameter estimates (relative standard error \& confidence intervals for CL, Vd and Ka) and predictive performance and robustness, per published (PMID: 27884052) and regulatory guidance (FDA guidance on Population Pharmacokinetics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/population-pharmacokinetics).

Population Pharmacokinetic (PK)/Pharmacodynamic (PD) Modeling will also enable exploratory investigation of the relationship between anakinra dose, concentration-time course in blood, and drug effects, both biomarkers of inflammation and clinical endpoints.

AP2 will recruit 24 infants born 24-28 weeks-GA, randomised to one of 3 dosing arms, 8 infants/arm, stratified to ensure balanced GA-distribution. Participants will otherwise receive standard care.

• Incidence of bronchopulmonary dysplasia [Time frame: 4 months.]
• Hammersmith infant neurological examination [Time frame: 6 months]
• Incidence of intracranial/intraventricular haemorrhage and peri-ventricular leukomalacia. [Time frame: 4 months]
• Safety of anakinra in extremely premature neonates. [Time frame: 4 weeks]
• Individual Total Clearance (CL) of anakinra in extremely premature neonates. [Time frame: From Baseline up to Day 21.]
• Individual Volume of Distribution (VD) of anakinra in extremely premature neonates. [Time frame: Baseline to Day 21.]
• Individual Absorption Rate Constant (Ka) of subcutaneously administered anakinra in extremely premature neonates. [Time frame: Day 14-21.]
• Individual Maximum Serum Concentration (Cmax) of anakinra. [Time frame: Baseline to Day 21.]
• Individual Area Under the Concentration-time Curve Within a Dosing Interval (AUCtau) of anakinra. [Time frame: Baseline to D21.]
• Individual Model - derived Ctrough Concentrations of anakinra. [Time frame: Baseline to D21.]